CN102670567A - Flux-enabling compositions and methods for dermal delivery of drugs - Google Patents

Flux-enabling compositions and methods for dermal delivery of drugs Download PDF

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Publication number
CN102670567A
CN102670567A CN2012101072262A CN201210107226A CN102670567A CN 102670567 A CN102670567 A CN 102670567A CN 2012101072262 A CN2012101072262 A CN 2012101072262A CN 201210107226 A CN201210107226 A CN 201210107226A CN 102670567 A CN102670567 A CN 102670567A
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China
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formulation
skin
volatile solvent
flux
oil
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CN2012101072262A
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Chinese (zh)
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J·张
K·S·华纳
S·莎玛
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扎尔斯制药公司
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Priority to US60/750,652 priority Critical
Priority to US75065205P priority
Priority to US75052305P priority
Priority to US75063705P priority
Priority to US60/750,637 priority
Priority to US60/750,523 priority
Priority to US79509106P priority
Priority to US60/795,091 priority
Application filed by 扎尔斯制药公司 filed Critical 扎尔斯制药公司
Priority to CN200680051627.32006.12.14 priority
Publication of CN102670567A publication Critical patent/CN102670567A/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7015Drug-containing film-forming compositions, e.g. spray-on
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0014Skin, i.e. galenical aspects of topical compositions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0014Skin, i.e. galenical aspects of topical compositions
    • A61K9/0017Non-human animal skin, e.g. pour-on, spot-on

Abstract

The invention relates to flux-enabling compositions and methods for dermal delivery of drugs. The present invention is drawn to adhesive solidifying formulations, methods of drug delivery, and solidified layers for dermal delivery of a drug. The formulation can include a drug, a solvent vehicle, and a solidifying agent. The solvent vehicle can include a volatile solvent system comprising at least one volatile solvent, and a non-volatile solvent system comprising at least one non-volatile solvent, wherein at least one non-volatile solvent is a flux-enabling non-volatile solvent(s) capable of facilitating the delivery of the drug at therapeutically effective rates over a sustained period of time. The formulation can have a viscosity suitable for application to a skin surface prior to evaporation of the volatile solvents system. When applied to the skin, the formulation can form a solidified layer after at least a portion of the volatile solvent system is evaporated.

Description

用于皮肤输送药物的促通量组合物及方法 Flux promoting compositions and methods for the transdermal delivery of drugs

[0001] 本申请为分案申请,原申请的申请日为2006年12月14日,申请号为200680051627. 3 (PCT/US2006/048061),发明名称为“用于皮肤输送药物的促通量组合物及 [0001] The present application is a divisional application filed parent application is December 14, 2006, Application No. 200680051627. 3 (PCT / US2006 / 048061), entitled "pro-drug delivery to the skin flux and composition

方法”。 method".

发明领域 Field of the Invention

[0002] 本发明一般地涉及为药物的皮肤输送开发的系统。 [0002] The present invention relates generally to drug delivery systems for the development of the skin. 更具体地,本发明涉及粘性固化制剂,其具有适合应用于皮肤表面的粘度,并且形成持续的药物输送粘性固化层。 More particularly, the present invention relates to a viscous curable formulation, having a viscosity suitable for application to the skin surface, and forming a sustained drug delivery tack cured layer. [0003] 发明背景 [0003] Background of the Invention

[0004] 常规的皮肤药物输送系统通常可以被分为两种形式:半固态制剂和皮肤贴剂剂型。 [0004] Conventional drug delivery systems of the skin can be generally divided into two forms: semi-solid formulations and dosage forms a skin patch. 半固态制剂有若干不同的形式,包括软膏剂、乳膏、泡沫、糊剂、凝胶或洗剂,并且局部地应用在皮肤上。 Semi-solid formulations of a number of different forms, including ointments, creams, foams, pastes, gels or lotions, and topical application to the skin. 皮肤(包括经皮)贴剂剂型也存在若干不同的形式,包括基质贴剂结构和储液贴剂结构。 Skin (including transdermal) patches are also several different dosage forms, the structure comprises a matrix patch and reservoir patch structure. 在基质贴剂中,活性药物在涂布于背膜(backing film)上的粘合剂中混合。 In matrix patches, the active drug backing film (backing film) on the adhesive applied to mixed. 掺有药物的粘合剂层通常直接应用于皮肤,并作为使所述贴剂粘附在皮肤上的工具和作为促进药物输送的贮器或载体而发挥作用。 Adhesive layer is typically doped with a drug is directly applied to the skin, and the patch adhere to the skin and the tool carrier as a reservoir or facilitate drug delivery functions as. 相反地,在储液贴剂中,药物通常被掺入由薄袋容纳的溶剂系统中,所述薄袋可以是薄的柔软容器。 In contrast, in the reservoir patches, the drug is generally incorporated in the solvent system accommodating a thin bag, the bag may be a thin sheet of flexible container. 所述薄袋可以包括用粘合剂涂布的可渗透或半透膜表面,所述粘合剂用于将所述膜粘贴于皮肤。 The bag may comprise a thin permeable or semi-permeable membrane surface coated with an adhesive, the adhesive film is attached to the skin. 所述膜通常是指速率限制膜(尽管它实际上可能并非在所有情况下在输送过程中都是速率限制性的)并能控制药物从所述薄袋内向皮肤的运输,用于皮肤输送。 The membrane generally refers to the rate limiting membrane (although it may not actually all the rate limiting during transport in all cases) and to control the drug from the bag to transport the thin skin for transdermal delivery.

[0005] 尽管贴剂和半固态制剂被广泛用于将药物输送入皮肤并输送穿过皮肤,但是他们都具有明显的局限性。 [0005] While the patch and semi-solid formulations are widely used for drug delivery and transport through the skin into the skin, but they have significant limitations. 例如,许多半固态制剂通常只含有在使用后立刻蒸发的挥发性溶剂(一种或多种),如水和乙醇。 For example, a number of semi-solid formulations generally contain only volatile solvent (s) used immediately after evaporation, water and ethanol. 这类溶剂的蒸发能够引起皮肤药物输送的明显降低或甚至是终止,这在多数情况下可能是不期望的。 Evaporation of such solvents can cause the skin for drug delivery is significantly reduced or even terminated, which in many cases may not be desirable. 一些传统的半固态制剂可能也含有一些不挥发的液态物质,它们被选出或配制,用于涂敷所述制剂或改进所述制剂的美感,而非以充足的通量输送药物。 Some conventional semi-solid formulations may also contain some non-volatile liquid substances, which are selected or formulated coating for improved aesthetics of the formulation or the formulation, rather than delivering a drug with sufficient flux. 那些制剂的药物输送可能不是足够的或持续性的。 Those pharmaceutical formulation delivery may not be sufficient or persistent. 此外,半固态制剂通常被“擦进(rubbed into)”皮肤中,这并不必然意味着药物制剂实际上被输送进皮肤中。 Further, semi-solid formulations are generally "rubbed into (rubbed into)" the skin, this does not necessarily mean that the pharmaceutical formulation is actually delivered into the skin. 相反,这个措词通常表示非常薄的一层药物制剂被应用于皮肤表面上,但仍在皮肤表面之外。 Instead, the phrase usually means a very thin layer of the pharmaceutical formulation is applied to the skin surface, but it is still outside of the skin surface. 应用于皮肤的传统半固态制剂的这类薄层可能不含有足量的活性药物,以在长时间段内实现持续输送。 Such thin skin is applied to a conventional semi-solid formulations may not contain a sufficient amount of active drug to achieve sustained delivery long period of time. 此外,由于与诸如衣服之类的物体接触,传统半固态制剂经常容易受到无意的去除,这可能对持续输送有害和/或不期望地弄脏衣服。 Further, due to contact with objects such as clothing or the like, the conventional semi-solid formulations are often susceptible to inadvertent removal, which may be harmful and / or undesirable stain clothing for sustained delivery. 存在于半固态制剂中的药物可能也会被无意地输送给与正在用局部半固态制剂进行治疗的对象接触的人。 Present in the semi-solid pharmaceutical formulations may also be delivered inadvertently given human subject being treated with a topical semi-solid formulation contacts.

[0006] 关于基质贴剂,为了被适当地输送,药物应该在粘合剂中具有足够的溶解度,原因在于仅溶解的药物主要地对皮肤渗透所需的驱动力有贡献。 [0006] For the matrix patch, in order to be properly conveyed, the drug should have a sufficient solubility in the adhesive, because the driving force is primarily only dissolved drug to the skin contributes to the desired penetration. 不幸的是,在粘合剂中过低的溶解度在持续期内不产生足够的皮肤渗透驱动力。 Unfortunately, the low solubility in the adhesive does not produce sufficient skin penetration of the duration of the driving force. 此外,可用于帮助药物溶解或增强皮肤渗透性的多种成分,如液体溶剂和渗透增强剂,可能不能以发挥作用的足够量掺入多种粘性基质系统中。 Further, the drug is dissolved or may be used to help enhance the skin permeability of more components, such as liquid solvents and permeation enhancers may not play a sufficient amount to be incorporated more adhesive matrix systems. 例如,在功能性水平,这些材料中的大多数可不良地改变粘合剂的耐磨性(wear property)。 For example, the functional level, most of these materials may undesirably alter the abrasion resistance (wear property) binder. 如此,基于粘合剂的基质贴剂中添加剂、增强剂、赋形剂等的选择和容许量可能受到限制。 Thus, the adhesive matrix patch based additives, reinforcing agents, excipients, etc. and the allowable amount of choice may be limited. 举例来说,对于许多药物,最优的经皮通量可以在药物溶于某种液体溶剂系统时达到,但是在典型基质贴剂中的粘合剂薄层通常不能包含治疗有效的、足够的适宜药物和/或添加剂。 For example, for many drugs, transdermal flux is optimal pharmaceutical dissolved in the liquid reaches a certain solvent system, but in a typical thin layer of adhesive matrix patches typically contain not therapeutically effective, a sufficient suitable drugs and / or additives. 而且,所述粘合剂的性质,如粘结性(coherence)和粘性(tackiness),也能够通过液态溶剂或增强剂的存在而得到显著改变。 Further, the adhesive properties, such as adhesion (Coherence) and tack (tackiness), it is possible by the presence of a liquid solvent or enhancers obtained significantly changed.

[0007] 关于储液贴剂,即使药物与所述贴剂的薄袋携带的特定液体或半固体溶剂系统相容,所述溶剂系统仍必须与渗透或半透膜上涂布的粘合剂层相容;否则所述药物可能受到粘合剂层的不良影响,或者所述药物/溶剂系统可能降低粘合剂层的粘性。 [0007] For a reservoir patch, even if the particular liquid medicament bags with the patch carrying a thin solid or semi-compatible solvent system, the solvent system must still be permeable or semipermeable membrane coated with an adhesive compatible layer; otherwise, the drugs may be adversely affected by the adhesive layer, or the drug / solvent system may reduce the viscosity of the adhesive layer. 除了这些剂型考虑,储库贴剂比基质贴剂体积更大并且通常制造更昂贵。 In addition to these considerations formulations, depot patch of a larger volume and is generally more expensive to manufacture than a matrix patch.

[0008] 皮肤(包括经皮)贴剂的另一个缺点是它们通常既不可拉伸也不柔软,原因在于背膜(在基质贴剂中)和薄的液袋(在储库贴剂中)通常由聚乙烯或聚酯制成,两者都是相对不可拉伸的材料。 [0008] The skin (including transdermal) patch Another disadvantage is that they typically neither stretched nor soft, because the backing film (the patch matrix) and a thin fluid bags (in the patch reservoir) usually it consists of polyethylene or polyester, both of which are relatively non-stretchable material. 如果所述贴剂应用于身体运动中明显拉伸的皮肤区域,如关节,可能发生贴剂和皮肤的分离,并因此对药物的输送有害。 If the patch is applied to an area of ​​skin in significant elongation of the body motion, such as joint, and separation of the skin patch may occur, and thus detrimental to the drug delivery. 此外,存在于皮肤表面的贴剂可在身体运动中阻碍皮肤的扩展并引起不适。 In addition, there is a patch on the skin surface may hinder the expansion of the skin in body movement and cause discomfort. 出于这些额外的原因,贴剂不是用在身体运动中易于扩展、弯曲和拉伸的皮肤区域的理想剂型。 For these additional reasons, a patch over an area of ​​skin is a dosage form used in the body motion is not easy to extend, bending and stretching.

[0009] 鉴于许多当前皮肤药物输送系统的缺点,理想的是提供系统、制剂和/或方法,其能够i)在长时间段内提供持续的药物输送;ii)不容易因为在应用期间与衣物、其它物体或人接触而引起无意除去;iii)能够应用于拉伸和扩展的皮肤区域而不引起不适或与皮肤接触较差;和/或iv)在应用和使用后能够轻易除去。 [0009] In view of the many disadvantages of current drug delivery system of the skin, it is desirable to provide a system, formulations and / or methods capable of i) providing a sustained drug delivery long period of time; ii) is not easy because the laundry during application , contact with other objects or persons caused unintentionally removed; iii) can be applied to an area of ​​skin stretch and expand without causing discomfort or poor contact with the skin; and / or iv) can be easily removed after application and use.

[0010] 发明概述 [0010] Summary of the Invention

[0011] 尽管成膜技术已经运用在化妆品和药物制备中,通常,这类系统中使用的溶剂在皮肤表面上并不能持续很长时间,因此对于持续释放应用并非最佳的。 [0011] While the film forming technique has been used in cosmetic and pharmaceutical preparations, in general, the solvent used in this type of system can not last long on the skin surface, so for sustained release applications not optimal. 根据这一点,本发明的发明人认识到挥发性溶剂以及促通量不挥发溶剂(flux-enabling non-volatilesolvent)在制剂中的使用可以改善或甚至最优化持续的药物输送。 According to this, the inventors of the present invention recognize a volatile solvent and a nonvolatile solvent to promote flux (flux-enabling non-volatilesolvent) used in the formulation may be improved or even optimized sustained drug delivery. 因此,有利的是以粘性固化组合物或制剂的形式提供皮肤输送制剂、系统和/或方法,所述粘性固化组合物或制剂具有适合应用于皮肤表面的粘度并且其在皮肤上形成药物输送固化层,所述药物输送固化层可以被轻易除去,如通过剥离或用溶剂清洗。 Thus, advantageously in the form of a viscous curable composition or formulation to provide a skin delivery formulation, system and / or method, the viscous curable composition or formulation having a viscosity suitable for application to the skin surface and which is formed on the solidified skin drug delivery layer, the drug delivery layer may be cured easily removed, such as by peeling or washing with solvent. 在一个实施方式中,所述粘性固化组合物或制剂一旦固化,可以是粘结性的。 In one embodiment, the viscous curable composition or formulation once cured, the adhesion may be.

[0012] 根据这一点,用于药物皮肤输送的固化制剂可以含有药物、溶剂载体和凝固剂。 [0012] can contain a pharmaceutical, a carrier solvent and coagulating agent according to this curing formulations for transdermal delivery of drugs. 所述溶剂载体可以包含具有一种或多种挥发性溶剂的挥发性溶剂系统和具有一种或多种不挥发溶剂的不挥发溶剂系统,其中所述不挥发溶剂系统含有至少一种用于所述药物的促通量不挥发溶剂,以便甚至是在大多数所述挥发性溶剂(一种或多种)蒸发以后,所述药物能在一段时间内以治疗有效量被输送。 The solvent may comprise a volatile solvent carrier system having one or more volatile solvents and having one or more non-volatile solvent system in the non-volatile solvent, wherein the non-volatile solvent system comprising at least for the promoting drug fluxes said non-volatile solvent, so even after the most volatile solvent (s) evaporating the drugs can be delivered in a therapeutically effective amount over a period of time. 所述制剂在至少一种挥发性溶剂蒸发之前可具有适合应用于皮肤表面的粘度,并且可以进一步被配置,使得当应用于皮肤表面时,所述制剂在至少一部分挥发性溶剂(一种或多种)蒸发后形成固化层,但在基本上固化之后仍持续输送药物。 The formulation of at least one volatile solvent prior to evaporation may have a viscosity suitable for application to the skin surface, and may further be configured such that when applied to the skin surface, at least a portion of the formulation a volatile solvent (one or more species) evaporated cured layer is formed, but after the delivery of a drug to substantially cure continued. 在一些实施方式中,所述固化层可以是粘结性的,以便其可从皮肤上剥离,或者是用溶剂可以从皮肤上洗去的。 In some embodiments, the cured layer may be a adhesive property, so that it can be peeled off from the skin, or can be washed with a solvent from the skin. 如本文所述,尽管可以使用许多其它药物类型,但在一个具体实施方式中,所述药物可以是性激素,而在另一个具体实施方式中,所述药物可以是抗抚(anti-wart)药物。 As described herein, can be used although many other types of drugs, but in a specific embodiment, the drug may be a hormone, and in another embodiment, the drug may be an anti-Fu (anti-wart) Drug . 所述凝固剂通常是在无塑化剂(plasticizing agent)(增塑剂(plasticizer))下形成刚性固体的聚合物。 The coagulant polymer is typically formed in a non-rigid solid plasticizer (plasticizing agent) (a plasticizer (plasticizer)) below. 因此,所述不挥发溶剂系统必须是所述凝固剂的增塑剂。 Thus, the non-volatile solvent system must be of the coagulant plasticizer.

[0013] 在一个可选的实施方式中,将药物皮肤输送至皮肤、皮肤内或穿过皮肤的方法可以包括在对象的皮肤表面施用制剂,其中所述制剂包括药物、溶剂载体和凝固剂。 [0013] In an alternative embodiment, the transdermal delivery of the drug to the skin, the skin, or through the skin may include a method of administering the formulation in the skin surface of the subject, wherein said pharmaceutical formulation comprises, a carrier solvent and the coagulating agent. 所述溶剂载体含有包括一种或多种挥发性溶剂的挥发性溶剂系统和包括一种或多种不挥发溶剂的不挥发溶剂系统,其中所述不挥发溶剂系统对于所述药物是促通量的。 The solvent carrier contains a volatile solvent system comprises one or more volatile solvents and solvent systems include one or more non-volatile non-volatile solvent, wherein the non-volatile solvent system to the flux of the drug is pro of. 在该实施方式中,所述制剂在所述挥发性溶剂系统蒸发之前可以具有适合应用并粘附在皮肤表面的粘度,并且所述制剂可以被应用以便在所述挥发性溶剂系统至少部分蒸发之后皮肤表面形成固化层。 In this embodiment, after the formulation prior to evaporation of the volatile solvent system can have a viscosity suitable for the application and adhesion of the skin surface, and the formulation may be applied to at least partial evaporation of the volatile solvent system cured layer formed on the surface of the skin. 额外的步骤包括在持续的时间段内,以治疗有效速率从所述固化层向所述对象皮肤输送药物,其中所述药物在所述挥发性溶剂系统基本上蒸发后继续被输送。 Additional steps include sustained period of time, a therapeutically effective delivery rate of the drug from the solidified layer to the skin of the subject, wherein the medicament continues to be conveyed after the system is substantially volatile solvent was evaporated. 在一些实施方式中,所述固化层可以是软的或可弯曲的、粘结的连续固体,并且可以通过剥离除去。 In some embodiments, the cured layer may be soft or flexible, bonded continuous solid, and may be removed by peeling.

[0014] 在另一个实施方式中,制备用于皮肤药物输送的制剂的方法可以包括以下步骤:选择适合皮肤输送的药物;选择或配制对于所选药物而言是促通量的不挥发溶剂或不挥发溶剂的混合物,选择与所述药物和所述不挥发溶剂相容的凝固剂,选择或配制与所述药物、所述不挥发溶剂和所述凝固剂相容的挥发性溶剂系统;以及把上述全部成分配制成制剂。 Method [0014] In another embodiment, the skin preparation for drug delivery formulations may comprise the steps of: selecting a drug suitable for transdermal delivery; selecting or formulating a pharmaceutical for the selected non-volatile solvent, in terms of promoting a flux or the mixture of non-volatile solvents, the drug and the selected non-volatile solvent compatible coagulant selected or formulated with said drug, a non-volatile solvent and the volatile solvent system compatible with the coagulating agent; and the formulated to dispense all of the above. 所述制剂在所述挥发性溶剂系统蒸发之前可以具有适合应用于皮肤表面的粘度,并且所述制剂可以被应用在所述皮肤表面,在至少一部分所述挥发性溶剂系统蒸发之后在那里形成固化层。 The formulation prior to evaporation of the volatile solvent system can have a viscosity suitable for application to the skin surface, and the formulation may be applied on the skin surface, there is formed a cured after at least a portion of the evaporation of the volatile solvent system Floor. 在该实施方式中,所述药物在所述挥发性溶剂系统基本上蒸发后仍以治疗有效量继续被输送。 In this embodiment, the drug after evaporation of the volatile solvent system is still basically a therapeutically effective amount continues to be conveyed.

[0015] 而在又一个实施方式中,输送药物的固化层可以含有药物、不挥发溶剂系统和凝固剂。 [0015] In yet another embodiment, the cured layer may contain a drug delivery of the drug, non-volatile solvent system and the coagulating agent. 所述不挥发溶剂系统可以包含至少一种促通量不挥发溶剂或对于所述药物而言促通量的不挥发溶剂的混合物。 The non-volatile solvent system may comprise a mixture of at least one non-volatile solvent or pro flux to the flux of the drug in terms of promoting non-volatile solvent. 所述固化层可以是软的粘结性固体,其被粘附在身体表面,并且当从这里皮肤输送至少一部分所述药物时,所述固化层至少基本上没有水和比水更具挥发性的溶剂,并且其中所述固化层对于所述药物而言是促通量的。 The curable adhesive layer may be a soft solid which is adhered to the surface of the body, and here, when at least a portion transdermal delivery medicament, the solidified layer at least substantially free of water and more volatile than water solvent, and wherein said curable layer is for the purposes of promoting the drug flux.

[0016] 本发明的额外特征和优点将通过以下以举例的方式阐述本发明的特征的详细描述和附图而变得明显。 [0016] Additional features and advantages of the invention will become apparent by way of example the following detailed description and drawings set forth the features of the present invention by.

[0017] 附图简述 [0017] BRIEF DESCRIPTION

[0018] 图I是根据本发明的实施方式从制剂穿过人尸体皮肤经皮输送的双氯酚酸的累积量随时间变化的图不,其中在28小时内表现出稳态输送。 [0018] Figure I is a human cadaver skin through the cumulative amount of diclofenac transdermal delivery changes with time from a formulation according to the embodiment of FIG no embodiment of the present invention, which exhibits a steady state transported within 28 hours.

[0019] 图2是根据本发明的实施方式从具有类似组成的制剂穿过人尸体皮肤经皮输送的罗哌卡因的累积量随时间变化的图示,其中在30小时内表现出稳态输送。 [0019] FIG. 2 is an embodiment of the present invention from the time the cumulative amount of ropivacaine formulation having a similar composition through human cadaver skin over illustrated transdermal delivery, which exhibits a steady state within 30 hours delivery.

[0020] 图3是根据本发明的实施方式从固化的粘性制剂穿过体外生物膜输送的睾酮的累积量随时间变化的图示,其比得上上市产品(AndroGel)。 [0020] FIG. 3 is illustrating the cumulative amount of biofilm through delivery of testosterone over time from the cured viscous formulation according to an embodiment of the present invention, which is comparable to market (AndroGel).

[0021] 图4是根据本发明的实施方式从两种单独制剂经皮输送的阿昔洛韦(acyclovir)的累积量随时间变化的图示,其比得上上市产品Zovirax乳膏。 [0021] FIG. 4 is a cumulative amount of acyclovir (acyclovir) according to an embodiment of the present invention is delivered from two separate formulations for transdermal illustrating changes over time, which is comparable to market Zovirax cream.

[0022] 优选实施方式详述 [0022] Detailed Description of preferred embodiments

[0023] 在本发明的具体实施方式被公开和描述之前,应该理解本发明不限于本文公开的具体过程和材料,因为它们在一定程度上可以有所变化。 [0023] Before particular embodiments of the present invention are disclosed and described, it should be understood that the present invention is not limited to the particular process and materials disclosed herein because they may vary to some extent. 也应该理解,本文所用的术语仅仅是出于描述具体实施方式的目的而使用,并非意欲限制,因为本发明的范围将仅由所附的权利要求及其等同物限定。 It should also be understood that, as used herein, the terms are merely for the purpose of describing particular embodiments of the use, not intended to be limiting, since the scope of the present invention will be limited only by the appended claims and their equivalents. [0024] 在描述和要求保护本发明的过程中,使用了以下术语。 [0024] In describing and claiming the present invention, the following terms are used.

[0025] 单数形式的“一个(一种)(a) ”、“一个(一种)(an) ”和“该(the) ”包括复数指代物,除非上下文中明确另外指出。 [0025] The singular forms "a (s) (A)", "A (s) (AN)" and "the (The)" include plural referents unless the context clearly dictates otherwise. 因此,例如提到“药物(a drug)”包括指代一种或多种这样的组合物。 Thus, for example, reference to "a drug (a drug)" includes reference to one or more of such compositions.

[0026] “皮肤”被定义为包含人的皮肤(完整的、患病的、溃疡的或破损的),手指和脚趾指甲表面,以及通常至少部分暴露于空气中的粘膜表面,如嘴唇、生殖器和肛门粘膜、以及鼻和口腔粘膜。 [0026] "skin" is defined as comprising human skin (intact, diseased, damaged, or ulcers), the surface of the finger and toe nails, and typically at least partially exposed to air mucosal surface, such as lips and genital and anal mucosa, and nasal and oral mucosa.

[0027] 术语“药物”是指为了达到治疗效果而应用在皮肤上、皮肤内或透过皮肤的任何生物活性剂。 [0027] The term "drug" refers to the application in order to achieve a therapeutic effect on the skin, the skin, or through the skin of any biologically active agent. 这包括传统上被鉴定为药物的组合物,以及在传统意义上一直不被认为是“药物”,但能为某些病症提供治疗效果的其它生物活性剂,如过氧化物、润湿剂、软化剂等。 This is traditionally identified as including pharmaceutical compositions, and has not been considered to be "drug" in the traditional sense, but other biologically active agents can provide a therapeutic effect, such as peroxides, wetting agents for certain disorders, softener. 当一般地提到“药物”时,应该理解,给定药物有不同的形式,并且那些不同的形式被明确包括在内。 When referring to "drug" In general, it should be appreciated that a given drug in different forms, and those different forms are explicitly included. 据此,各种药物形式包括多晶型物、盐、水化物、溶剂化物和共结晶体。 Accordingly, various pharmaceutical forms include polymorphs, salts, hydrates, solvates and co-crystals. 对于一些药物,药物的一种物理形式可能具有更好的物理-化学性质,使其更易于接触、进入或穿透皮肤,并且这种特定的形式被定义为有利于皮肤输送的物理形式。 For some drugs, one physical form of the drug may have better physical - chemical properties, making it easier to contact or penetrate into the skin, and this forms a particular physical form is defined as the delivery of beneficial to the skin. 例如,通过促通量不挥发溶剂的双氯酚酸钠的稳态通量比通过相同促通量不挥发溶剂的双氯酚酸的稳态通量高得多。 For example, a steady state flux of diclofenac sodium in non-volatile solvent by promoting the steady state flux does not pass than the volatilization of the solvent by the same pro-diclofenac flux much higher. 因此,期望的是,评价通过不挥发溶剂的药物物理形式的通量,以选择期望的物理形式/不挥发溶剂的组合。 Accordingly, it is desirable that the evaluation of physical forms of drug flux evaporation of the solvent, to select a desired physical form / nonvolatile combination of solvents.

[0028] 短语“皮肤药物输送”或“药物(一种或多种)的皮肤输送”可包括经皮药物输送和局部药物输送,并包括药物(一种或多种)输送到、穿透或进入皮肤。 [0028] The phrase "skin drug delivery" or "drug (one or more) of the transdermal delivery" may include a transdermal drug delivery and topical drug delivery, and comprising a drug (s) delivery to, penetration or into the skin. 药物的“经皮输送”可以被靶向紧在皮肤之下的皮肤组织、皮肤下的局部组织或器官、体循环和/或中枢神经系统。 Drug "transdermal delivery" can be targeted skin tissue immediately below the skin, local tissue or organ, circulation, and / or central nervous system under the skin. “局部输送”包括药物输送到皮肤组织,及随后可能发生的吸收进深层组织。 "Local delivery" includes drug delivery to the skin, and possible subsequent absorption into the deeper tissues.

[0029] 术语“通量(flux) ”,如分别在文中的“皮肤通量”或“经皮通量”,是指每单位时间每单位面积渗透进入或穿过皮肤的药量。 [0029] The term "flux (Flux)", respectively, in the text as "skin flux" or "transdermal flux" means per unit time per unit area of ​​the penetration into or through the skin dose. 通量的典型单位是微克每平方厘米每小时。 Typical flux unit is micrograms per square centimeter per hour. 测量通量的一个方法是将所述制剂置于人类志愿者的一块已知皮肤区域上并测量在某个时间段内有多少药物可以渗透进入或穿过皮肤。 A method of measuring the flux formulation is placed human volunteers and a known area of ​​skin to measure how much medicament can penetrate into or through the skin in a certain period of time. 多种方法(体内方法)也可以用于测量。 Various methods (in vivo method) may also be used for measurement. 实施例I中描述的方法或其它相似的方法(体外方法)也可以用于测量通量。 The method described in Example I or other similar methods (in vitro methods) may also be used to measure the flux. 尽管体外方法采用从尸体获得的人表皮膜或从无毛小鼠新分离的皮肤组织,而非利用人类志愿者测量穿过皮肤的药物通量,本领域普通技术人员一般接受:适当设计并在体外进行的测试结果可以用于以合理的可靠性估计或预测体内测试的结果。 Although in vitro methods using human epidermal membrane obtained from cadavers or freshly isolated hairless mouse skin tissue never, rather than using the drug flux through the skin of human volunteers measurement, those of ordinary skill in the art generally accepted: appropriately designed and the test results may be used for in vitro results with reasonable reliability estimate or predict the in vivo testing. 因此,在本专利申请中提到的“通量”值可以表示体内或体外方法测量的值。 Thus, mentioned in this patent application, "flux" value may represent the value measured in vivo or in vitro methods.

[0030] 关于不挥发溶剂系统(或包含不挥发溶剂系统的固化层)的术语“促通量(flux-enabling)”是指具体选择或配制以能够为特定药物(一种或多种)提供治疗有效通量的不挥发溶剂系统(包括一种或多种不挥发溶剂)。 [0030] For the non-volatile solvent system (or cured layer comprises non-volatile solvent system), the term "pro-flux (flux-enabling)" means that a particular selected or formulated so as to provide for the particular drug (s) a therapeutically effective flux non-volatile solvent system (comprising one or more non-volatile solvents). 对于局部地或区域性地输送药物,促通量不挥发溶剂系统被定义为这样的不挥发溶剂系统:当所述不挥发溶剂系统用所述药物饱和时,在没有任何其它成分的帮助下,不挥发溶剂系统单独能够输送治疗上充足水平的药物穿过、到达或进入对象皮肤。 For topical or regional delivery of drugs, non-volatile solvent system to promote the flux is defined as a non-volatile solvent system: when the non-volatile solvent system was saturated with the medicament, without any help of other components, separate non-volatile solvent system capable of delivering a therapeutically sufficient levels of the drug through, to or into the subject's skin. 对于全身靶向的药物,促通量不挥发溶剂系统是这样的不挥发溶剂系统:当不挥发溶剂系统用所述药物饱和且与对象的皮肤在不大于500cm2的接触面积上完全接触时,其能够在24小时中提供治疗上充足的日剂量。 For systemic targeted drug, pro-flux nonvolatile solvent system is a non-volatile solvent system: when the contact area with the non-volatile solvent system and the drug is saturated and skin of the subject not greater than 500cm2 full contact, which It can provide sufficient daily dose of the treatment in 24 hours. 优选地,不挥发溶剂系统的接触面积不大于100cm2。 Preferably, the contact area of ​​the non-volatile solvent system is not more than 100cm2. 使用这种饱和的药物在溶剂中(drug-in-solvent)的状态的测试可以用于测量不挥发溶剂系统的最大通量产生能力。 Use of such a solvent saturated with the test drug (drug-in-solvent) may be used in a state where the maximum flux measurement without the ability to produce volatile solvent system. 要确定通量,所述药物溶剂混合物需要在皮肤上保持临床上足够量的时间。 To determine the flux, a solvent mixture of the drug needs to maintain a sufficient amount of time on the skin clinically. 实际上,在延长的一段时间内使液体溶剂保持在人类志愿者的皮肤上可能是困难的。 In fact, the liquid solvent to remain on the skin of human volunteers may be difficult for an extended period of time. 因此,确定溶剂系统是否是“促通量的”的一种可选方法是使用实施例I中描述的设备和方法测量通过无毛小鼠皮肤或人尸体皮肤的体外药物渗透。 Accordingly, it is determined whether the system is an alternative solvent method "pro-flux" is using the apparatus and method described in Example I was measured by non-pharmaceutical in vitro human cadaver skin or hairless mouse skin permeation. 本领域普通技术人员通常使用该方法和类似的方法评价制剂的渗透性和可行性。 Those of ordinary skill in the art and generally permeability evaluation of the feasibility of using the same formulation and similar methods. 可选地,不挥发溶剂系统是否是促通量的可以用这样的方法在活的人体对象的皮肤上测试,所述方法在皮肤上维持具有饱和药物的不挥发溶剂系统,而这样的方法对产品来说可能是不实际的。 Alternatively, if the non-volatile solvent system is a pro-throughput methods can be used in such a skin test living human subject, said method for maintaining non-volatile solvent system having a saturated drug on the skin, and a method of products, may not be practical. 例如,具有饱和药物的不挥发溶剂系统可以被吸收进吸收性织物材料,所述材料随后被应用于皮肤并用保护膜覆盖。 For example, non-volatile solvent system having a saturated drug may be absorbed into the absorbent fabric material, the material is then applied to the skin and covered with a protective film. 这样的系统作为药品是不实用的,但是适合测试不挥发溶剂系统是否具有提供充足的药物通量的内在能力,或其是否促通量。 Such a system is not practical as a pharmaceutical, but are not suitable for testing whether the volatile solvent system to provide adequate drug fluxes inherent ability, whether to promote or flux.

[0031] 也注意到,一旦所述制剂形成固化层,在部分不挥发溶剂仍保留在固化层中时,甚至在挥发性溶剂(包括水)已经基本上蒸发后,所述固化层对所述药物来说也可以是“促通量的”。 [0031] Also note that once the formulation cured layer is formed, evaporation of the solvent does not remain in the cured layer in the part, even in a volatile solvent (including water) has been substantially evaporated, a cured layer of the it can also be a drug "to promote flux."

[0032] 短语“有效量”、“治疗有效量”、“治疗有效速率”或类似的,当其涉及药物时,是指在治疗一种为其输送药物的病症中,达到任何可测量水平的治疗结果的充足的药物量或药物输送速率。 [0032] The phrase "effective amount", "therapeutically effective amount", "therapeutically effective rate" or the like, as it relates to medicaments for the treatment of one means of delivery of a drug disorder, achieve any measurable level of sufficient amount or a result of drug treatment drug delivery rate. 应该理解,“可测量水平的治疗结果”可能满足或可能不满足任何政府机构批准产品商业化时的效能标准。 It should be understood that "treatment outcome measurable levels" may or may not meet any government to meet the approval criteria of the effectiveness of product commercialization. 应该理解,各种生物因素可能影响物质执行其预期任务的能力。 It should be understood that various biological factors ability of a substance to perform its intended task may be affected. 因此,“有效量”、“治疗有效量”或“治疗有效速率”在某些情况下可在某种程度上取决于这些生物因素。 Thus, an "effective amount", "therapeutically effective amount" or "therapeutically effective rate" may in some cases depend on such biological factors to some degree. 然而,对每种药物,本领域普通技术人员对于大多数对象中充足的剂量或通量范围方面通常存在共识。 However, for each drug, those of ordinary skill in the art for most objects in a sufficient dose or flux scope usually present consensus. 而且,尽管治疗效果的实现可以由医生或其他合格的医务人员使用本领域已知的评价进行测量,但是应该认识到,个体差异和对治疗的反应可能使治疗效果的实现成为一个主观的决定。 Moreover, despite the therapeutic effect can be measured using known in the art evaluation by a doctor or other qualified medical personnel, it should be recognized, and individual differences in response to treatment may become the therapeutic effect of a subjective decision. 治疗有效量或输送速率的确定对药物科学和医学领域的普通技术人员是公知的。 Determination of a therapeutically effective amount or delivery rate of ordinary skill in the pharmaceutical and medical fields of science and are well known.

[0033] “治疗有效通量”被定义为所选药物的渗透通量,其输送临床上有益的足量药物进入或穿过皮肤,因为一些患者群体能够从所述药物通量中获得一定程度的益处。 [0033] "therapeutically effective flux" is defined as the flux of the selected medicament, the delivery of a clinically sufficient amount of beneficial drugs into or through the skin, since some patient populations can be obtained to some extent from the drug flux benefits. 它并不一定表示大多数患者群体能够获得一定程度的益处,或所述益处高至足以被相关政府机构或医药职业认为是“有效的”。 It does not necessarily mean that the majority of the patient population can benefit to some extent, or the benefits of high enough to be relevant government agencies or medical profession considered to be "effective." 更特别地,对于靶向皮肤或接近皮肤表面的局部组织或器官(如关节,某些肌肉,或至少部分在皮肤表面5cm内的组织/器官),“治疗有效通量”是指能够在临床上合理的时间内输送足量药物进入目标组织的药物通量。 More particularly, for a targeted skin or near the surface of the skin or organs of local tissue (e.g., joint, certain muscles, or at least partially at the surface of the skin tissue / organ within 5cm), "therapeutically effective flux" refers to the clinical drug flux sufficient amount of the drug delivery into the target tissue within a reasonable time. 对于靶向体循环的药物,“治疗有效通量”是指通过临床上合理的皮肤接触面积能够在临床上合理的时间内输送足量所选药物,以产生临床上有利的血浆或血液药物浓度的药物通量。 Circulation for targeted drug "therapeutically effective flux" refers to the delivery through a skin contact area of ​​reasonable clinically reasonable time clinically sufficient amount of the selected drug to produce a favorable clinical drugs or blood plasma concentration drug flux. 临床上合理的皮肤接触面积被定义为大部分受治疗者将接受的皮肤应用面积的大小。 Reasonable skin contact area is defined as the most clinically size of the skin area of ​​the subject application will be accepted. 典型地,等于或小于400cm2的皮肤接触面积被认为是合理的。 Typically, less than or equal to 400cm2 of skin contact area is considered to be reasonable. 因此,为了经由400cm2的皮肤接触面积在10小时内向体循环输送4000mcg的药物,通量需要至少为4000mcg/400cm2/10小时,等于lmcg/cm2/hr。 Accordingly, the contact area of ​​400 cm2 of the skin to the systemic circulation over a period of 10 hours of delivery of the drug 4000mcg, the flux is at least 4000mcg / 400cm2 / 10 hours via equal lmcg / cm2 / hr. 通过这个定义,不同的药物具有不同的“治疗有效通量”并且在不同的受治疗者间可以不同,或甚至对于相同的受治疗者在不同的时间可以不同。 By this definition, different drugs have different "therapeutically effective flux" and may be different between different subjects, or even for the same subject can be different at different times. 然而,对于每种药物,本领域普通技术人员在对大多数受治疗者在大多数时间充足的剂量或通量范围方面通常存在共识。 However, for each drug, those of ordinary skill in the art to most aspects of a subject in a dose sufficient most of the time or throughput range commonly found consensus.

[0034] 以下是对某些药物治疗有效的或大于足量的通量的估计: [0034] The following are valid for certain medications or greater than a sufficient amount of the flux estimate:

[0035] 表A——多种药物的体外稳态通量值[0036] [0035] Table A-- more drugs in vitro steady state flux values ​​[0036]

Figure CN102670567AD00101

[0037] *使用实施例I中所述的体外方法确定的通量 [0037] * using the in vitro method described in Example I to determine flux

[0038] **基于相对于利多卡因的已知效能估计的通量 [0038] * based on the known efficacy with respect to the estimated flux of lidocaine

[0039] 表A中的治疗有效通量值(除了罗哌卡因)代表了在实施例I所描述的体外系统 [0039] A therapeutically effective flux values ​​in the table (except ropivacaine) represents Example I in vitro system described in

中上市产品穿透无毛小鼠或人表皮膜的稳态通量值。 Market penetration in the hairless mouse or human epidermal membrane steady state flux values. 这些值仅表示估计值并提供了制剂开 These values ​​represent only estimates and provides formulations opening

发和优化的比较基础。 Development and optimization of the basis for comparison. 所选药物的治疗有效通量对于要治疗的不同疾病、疾病的不同阶段 A therapeutically effective flux of the drug selected for different stages of different diseases to be treated, the disease

和不同的个体受治疗者大不相同。 And different individuals subject very different. 应该注意,所列的通量可能大于治疗有效通量。 It should be noted that the flux listed may be greater than a therapeutically effective flux.

[0040] 下列在表B中所列的例子显示了不挥发溶剂对一些特别研究的药物的促通量能 [0040] In the examples listed in the following Table B shows the non-volatile solvent for some drugs, particularly studies promoting energy flux

力的筛选。 Screening force. 实验如下文中实施例I所述进行并且结果进一步在后续实施例2-9中讨论。 As described in Experimental Example I for the results of Examples 2-9 and discussed further in a subsequent embodiment.

[0041 ] 表B—来自不挥发溶剂系统的各种药物的体外稳态通量值 In vitro steady state flux values ​​[0041] Table B- drugs from various non-volatile solvent system

[0042] [0042]

Figure CN102670567AD00102

[0043] [0043]

Figure CN102670567AD00111

[0044] *每个数值代表三次测定的平均值和标准偏差 [0044] * Each value represents the mean of triplicate determinations and standard deviation

[0045] 表B中来自不挥发溶剂的体外稳态通量值显示出令人吃惊的促通量溶剂和非促通量溶剂。 [0045] Table B shows the surprising solvent and non-pro-pro flux from the flux in vitro steady state flux values ​​solvent nonvolatile solvent. 这些信息可以用于指导制剂的开发。 This information can be used to guide the development of formulations.

[0046] 关于促通量不挥发溶剂(一种或多种)的术语“增塑(或塑化)”被定义为在凝固剂中发挥增塑剂作用的促通量不挥发溶剂。 [0046] For promoting the flux is not a volatile solvent (s), the term "plasticizing (or plasticized)" is defined as a plasticizer play a role in the coagulation pro flux nonvolatile solvent. “增塑剂”是在所述挥发性溶剂系统已经至少基本上蒸发后,能够增加制剂延伸百分比的试剂。 "Plasticizer" after the system has been at least substantially volatile solvent was evaporated, the formulation can be increased percent elongation agent. 增塑剂也具有通过使其更柔软和/或更有弹性来降低固化制剂脆性的能力。 The plasticizer has the ability to reduce the brittleness of the cured formulation by making it softer and / or more elastic. 例如,丙二醇是用于以聚乙烯醇作为所选的凝固剂的药物酮洛芬的“促通量的、塑性不挥发溶剂”。 For example, propylene glycol for ketoprofen polyvinyl alcohol as a coagulant selected "to promote flux, plastic non-volatile solvent." 然而,以Gantrez S-97或Avalure UR 405作为凝固剂的酮洛芬制剂中的丙二醇不提供相同的增塑效果。 However, with the Gantrez S-97 or Avalure UR 405 as a coagulating agent ketoprofen formulation in propylene glycol does not provide the same plasticizing effect. 丙二醇与Gantrez S-97或Avalure UR 405的组合不太相容,并导致对局部应用不太理想的制剂。 Propylene glycol in combination with Gantrez S-97 or Avalure UR 405 is less compatible, and result in less desirable formulation for topical application. 因此,给定的不挥发溶剂是否是“增塑的”取决于选择何种凝固剂。 Thus, a given non-volatile solvent is "plasticized" which depends on the choice coagulant.

[0047] 不同的药物通常具有不同的匹配促通量不挥发溶剂系统,所述系统提供特别良好的结果。 [0047] Typically different drugs have different matching flux pro nonvolatile solvent, the system provides particularly good results. 这样的例子列于表C。 Such examples are listed in Table C. 实验按照下文实施例I所述进行,并且结果在后续实施例2-9中进一步讨论。 Experimental Example I as described below for the embodiment, and the results are discussed further in a subsequent embodiment examples 2-9.

[0048] 表C—通过特别高促通量不挥发溶剂系统的各种药物体外稳态通量值 [0048] Table C- particularly high in vitro by a variety of pro-drugs of non-volatile solvent system throughput steady state flux values

[0049] [0049]

Figure CN102670567AD00112

[0050] *每个数值代表三次测定的平均值和标准偏差 [0050] * Each value represents the mean of triplicate determinations and standard deviation

[0051] 应该注意“促通量不挥发溶剂”、“促通量塑性不挥发溶剂”或“高促通量不挥发溶剂”可以是单一的化学物质或两种或多种化学物质的混合物。 [0051] It should be noted that "non-volatile solvent to promote flux", "flux promoting plasticity nonvolatile solvent" or "pro-high throughput nonvolatile solvent" may be a single chemical species or a mixture of two or more chemical substances. 例如,表C中丙酸氯倍他索的稳态通量值为9 : I的丙二醇:异硬脂酸混合物,这比单独的丙二醇或ISA产生高得多的氯倍他索通量(见表B)。 For example, Table C clobetasol propionate steady state flux values ​​9: I propylene glycol: isostearic acid mixture, which produced much higher clobetasol flux than either propylene glycol or ISA (see table B). 因此,9 : I的丙二醇:异硬脂酸混合物是“高促通量不挥发溶剂”,但单独的丙二醇或异硬脂酸不是。 Thus, 9: I propylene glycol: isostearic acid mixture is a "high-throughput promote non-volatile solvent", but alone is not isostearate or propylene glycol.

[0052] 当提到固化层时,术语“粘合”在这里是指固化层与皮肤之间足够的粘着力,以便所述层在大多数受治疗者上的预期使用中不会从皮肤上脱落。 [0052] When referring to the cured layer, the term "bonded" herein refers to a sufficient adhesion between the solidified layer and the skin, so that the layer on the intended use of the subject does not suffer from most of the skin off.

[0053] 用于描述固化层时,“粘性的”表示固化层粘附于体表,初始制剂层一开始被应用于所述体表上(在挥发性溶剂蒸发之前)。 [0053] When used to describe a solidified layer, "sticky" means a solidified layer adheres to the surface, the initial formulation layer is initially applied to the body surface (prior to evaporation of volatile solvent). 在一种实施方式中,它不表不所述固化层在相反的一侧是粘性的。 In one embodiment, the table it does not cure the layer on the opposite side is adhesive. 此外,应该注意,固化层能否在期望长的时间段内粘附于人体表面部分取决于身体表面的状况。 Further, it should be noted that, whether cured layer over a long period of time adhered to the surface of a desired part of the human body surface depending on the condition. 例如,过度出汗或油性皮肤、或皮肤表面的油性物质可使得所述固化层不太粘于皮肤上。 For example, excessive sweating or oily skin, oily substance or the skin surface may be such that the cured layer is not sticky to the skin. 因此,本发明所述的粘性固化层可能不能够在任意的身体表面条件下,在持续的一段时间中为每一个受治疗者维持与身体表面的完好接触并输送药物。 Thus, the adhesive cured layer of the present invention may not be able at any surface condition of the body, a sustained period of time to maintain good contact with the body surface of the subject for each person and delivery of a drug. 标准是其在身体表面和外部环境的正常条件下,在特定的时间段内对大多数受治疗者来说,与身体表面的大部分,如总面积的70%,保持良好接触。 Standard which under normal conditions is the body surface and the external environment, for the majority of a subject, and most, such as 70% of the total body surface area, maintain good contact in a specific period of time.

[0054] 术语“柔软的”、“有弹性的”、“弹性”等,如本文所使用,是指固化层的足够弹性,使得如果其在至少一个方向上被拉伸达约5%,并且通常达约10%或甚至更多,所述固化层不破裂。 [0054] The term "flexible" and "elastic", "elastomeric" and the like, as used herein, refers to a sufficient elasticity of the cured layer, such that if it is stretched in one direction at least up to about 5%, and typically up to about 10% or even more, the cured layer is not broken. 例如,显示出可接受的弹性和对皮肤粘性的固化层能够附着在可弯曲的皮肤部位,如肘、手指、腕、颈部、下背部、唇、膝部等,并在皮肤拉伸时,在皮肤上保持基本完整。 For example, when showing flexibility and acceptable skin tack cured layer can be adhered to the skin site may be bent, such as elbows, fingers, wrists, neck, lower back, lips, knees, etc., and stretched in the skin, remains substantially intact on the skin. 应该注意到,本发明所述的固化层在某些实施方式中并非必须具有任何弹性。 It should be noted that, according to the present invention, the cured layer in some embodiments need not have any elastic.

[0055] 术语“可剥离”,当用于描述固化层时,表示所述固化层能够以一大块或若干大块从皮肤表面提起,与许多小块或碎片相反。 [0055] The term "release", when used to describe the solidified layer, indicating that the cured layer can be lifted from the skin surface with a plurality of chunk or chunks, with many small fragments or vice versa.

[0056] 术语“持续的”涉及在至少30分钟的连续时间段内,并且在某些实施方式中,在至少约2小时、4小时、8小时、12小时、24小时或更长的时间段内,皮肤药物输送的治疗有效速率。 [0056] The term "continuous" refers to a continuous period of at least 30 minutes, and in some embodiments, at least about 2 hours, 4 hours, 8 hours, 12 hours, 24 hours or longer period the skin of a therapeutically effective drug delivery rates.

[0057] 当提到挥发性溶剂的蒸发时,术语“基本上”的使用表示包含在初始制剂中的挥发性溶剂的大部分已经蒸发。 [0057] When referring to evaporation of volatile solvent, the term "substantially" indicates that most of the volatile solvent contained in the initial formulation has evaporated. 相似地,当固化层被称作“基本上没有”包括水在内的挥发性溶剂时,,固化层具有总体上在所述固化层中小于10% wt,并且优选小于5% wt的挥发性溶剂。 Similarly, when the cured layer is referred to as "substantially free" volatile solvent including water ,, cured layer having a volatility generally less than 10% wt of the solidified layer, and preferably less than 5% wt of solvent.

[0058] “挥发性溶剂系统”可以是单一溶剂或挥发性溶剂的混合物,包括水和比水更具挥发性的溶剂。 [0058] "volatile solvent system" may be a single solvent or a mixture of volatile solvents, including water and a solvent more volatile than water. 可以用在本发明中的挥发性溶剂的非限制性例子包括乙酸异戊酯、变性酒精、甲醇、乙醇、异丙醇、水、丙醇、C4-C6烃、丁烷、异丁烯、戊烷、己烷、丙酮、氯丁醇、乙酸乙酯、氟-氯代烃、松节油、甲基乙基酮、甲醚、氢氟烃(hydrofluorocarbon)、乙醚、1,1,1,2-四氟乙烷、1,1,1,2,3,3,3_七氟丙烷、1,1,1,3,3,3-六氟丙烷、或它们的组合。 Non-limiting examples of volatile solvent may be used in the present invention include iso-amyl acetate, denatured alcohol, methanol, ethanol, isopropanol, water, propanol, C4-C6 hydrocarbons, butane, isobutene, pentane, hexane, acetone, chlorobutanol, ethyl, fluoro - chlorinated hydrocarbons, turpentine, methyl ethyl ketone, dimethyl ether, hydrofluorocarbons (hydrofluorocarbon), diethyl ether, ethyl 1,1,1,2-tetrafluoroethane alkoxy, 1,1,1,2,3,3,3_ heptafluoropropane, 1,1,1,3,3,3-hexafluoropropane, or combinations thereof.

[0059] “不挥发溶剂系统”可以是单一溶剂或挥发性低于水的溶剂的混合物。 [0059] "Non-volatile solvent system" may be a single solvent or a mixture of solvents less volatile than water. 它也可以包含室温下固态或液态的物质,如PH或离子对试剂。 It may also comprise a liquid or solid material at room temperature, such as ion-pairing reagent or PH. 所述挥发性溶剂系统蒸发后,所述不挥发溶剂系统的大部分应该保留在固化层中一定量的时间,足够以充足的通量皮肤输送药物到达、进入或穿过受治疗者的皮肤一段时间,以提供治疗效果。 After evaporation of the volatile solvent system, most of the non-volatile solvent system in the solidified layer should retain a certain amount of time sufficient enough to reach the flux transdermal delivery of drugs, into or through the subject's skin some time, to provide a therapeutic effect. 在一些实施方式中,为了获得活性药物的理想渗透性和/或与凝固剂或制剂中其它成分的相容性,两种或多种不挥发溶剂的混合物可以用于形成所述不挥发溶剂系统。 In some embodiments, the active agent in order to obtain desired permeability and / or coagulating agent or formulation compatibility with other ingredients, a mixture of two or more non-volatile solvents may be used to form the non-volatile solvent system . 在一种实施方式中,两种或多种不挥发溶剂的组合形成溶剂系统为药物提供了比每种不挥发溶剂各自为该药物提供的通量更高的经皮通量。 In one embodiment, the combination of two or more solvents forming a non-volatile solvent system to provide a higher throughput than the transdermal flux of each non-volatile solvent for the drug provided by each drug. 所述不挥发溶剂系统也可发挥固化层增塑剂的作用,以便所述固化层是有弹性的和柔软的。 The non-volatile solvent system can also play the role of a plasticizer cured layer, so that the solidified layer is resilient and soft.

[0060] 术语“溶剂载体”描述包含挥发性溶剂系统和不挥发溶剂系统的组合物。 [0060] The term "solvent carrier" describes a solvent system comprising volatile and non-volatile solvent composition system. 挥发性溶剂系统被选择,以便从粘性可剥离制剂中迅速蒸发,形成固化层,并且所述不挥发溶剂系统被配制或选择,以便在挥发性溶剂系统蒸发后,基本上保留作为所述固化层的一部分,以提供所述药物的持续输送。 Volatile solvent system is selected so as to be peeled from the adhesive formulation rapidly evaporated to form a cured layer, and the non-volatile solvent system is formulated or selected so that after evaporation of the volatile solvent system, the solidified layer substantially retained as part, to provide sustained delivery of the drug. 典型地,所述药物总体上可以部分或完全溶解在溶剂载体或制剂中。 Typically, the medicament may generally be partially or completely dissolved in the solvent vehicle or formulation. 同样,一旦挥发性溶剂系统蒸发,所述药物也能够部分或全部溶解在不挥发溶剂系统中。 Similarly, once the evaporation of the volatile solvent system, the drug can be partially or completely dissolved in the non-volatile solvent system. 挥发性溶剂系统蒸发后,药物仅部分溶剂在不挥发溶剂系统中的制剂具有保持更长持续输送时间的潜力,因为未溶解药物可以随着已溶解药物在药物输送过程中从固化层中耗尽而溶解在不挥发溶剂系统中。 After evaporation of the volatile solvent system, the solvent is only partially pharmaceutical formulation in the solvent system having a non-volatile maintained for a longer duration in time of delivery potential because the drug undissolved drug may be depleted from the cured layer with the dissolved drug delivery process dissolved in the non-volatile solvent system.

[0061] 关于固化层的术语“粘性”表示其粘附在原始制剂应用的皮肤上,而不必要,且优选地在另一侧不粘附在其它物体上。 [0061] The term & about cured layer "sticky" represents adhered to the skin of the original application of the preparation, but not necessary, and preferably on the other side does not adhere to other objects.

[0062] 一些实施方式中的“粘性固化制剂”、“固化制剂”或“制剂”是指在其挥发性溶剂(一种或多种)蒸发之前,具有适合应用在皮肤表面的粘度,并在至少部分挥发性溶剂(一种或多种)蒸发后成为固化层的组合物。 [0062] Some embodiments of the "sticky curing agents", "cure formulation" or "formulation" refers to a volatile solvent before it (one or more) and evaporated to a viscosity suitable for use with the skin surface, and at least a portion of the volatile solvent (s) after evaporation of the composition becomes cured layer. 所述固化层,一旦形成,可以是非常耐久的。 The solidified layer, once formed, can be very durable. 在一个实施方式中,一旦在皮肤表面固化,所述制剂可以形成揭片。 In one embodiment, the skin surface upon curing, exposing the formulation may be formed sheet. 这样的揭片可以是柔软、粘结的固体,其可以通过从皮肤上剥离多个相对于所应用制剂的大小的大片而去除,并且通常可以以单一的一片从皮肤上剥离。 Exposing Such sheet may be soft, solid adhesive which can be applied to the large size of the formulation is removed by peeling from the skin with a plurality, and typically may be a single peeled from the skin. 应用粘度通常比水样液体粘性更高,但粘性比软固体更低。 Application viscosity is generally higher than the viscosity of water-like liquid, but less viscous than a soft solid. 优选的粘质的例子包括具有与软膏剂、凝胶、糊剂等相似稠度的材料,如流动但不会溢流的粘稠液体。 Examples of preferred clay comprises a material having a similar consistency of an ointment, gel, paste or the like, but does not flow as a viscous liquid to overflow. 因此,当组合物被称为具有“适合应用”于皮肤表面的粘度时,这表示所述组合物具有足够高的粘度,以便应用于皮肤后,所述组合物基本上不从皮肤上流掉;但同时也具有足够低的粘度,以便其能够容易地涂布在皮肤上。 Thus, when the composition is referred to as having a "suitable for use" when the viscosity of the skin surface, which means that the composition has a sufficiently high viscosity to be applied to the skin, the composition does not substantially run off the skin; but also it has a sufficiently low viscosity so that it can be easily applied to the skin. 满足这一定义的粘度范围可以从约IOOcP到约3,000, OOOcP (厘泊),并且更优选从约1,OOOcP到约1,000, OOOcP0 Meet this definition IOOcP viscosity may range from about to about 3,000, OOOcP (centipoise), and more preferably from about 1, OOOcP to about 1,000, OOOcP0

[0063] 在本发明的一些实施方式中,可以期望的是,向所述制剂中加入额外的试剂或物质,以便提供增强或增加的粘性特征。 [0063] In some embodiments of the present invention, it may be desirable, additional agent or substance to the formulation, to provide enhanced or increased viscosity characteristics. 该额外的粘合试剂或物质可以是额外的不挥发溶剂或额外的凝固剂。 The additional adhesive agent or substance can be an additional non-volatile solvents or additional coagulants. 可以用作额外粘性增强剂的物质的非限制性例子包括甲基•乙烯基醚与马来酐的共聚物(Gantrez聚合物)、聚乙二醇和聚乙烯吡咯烷酮的共聚物、明胶、低分子量聚异丁烯橡胶、acrylsan烧基/辛基丙烯酰胺(acrylsan alkyl/octylacrylamido)共聚物(Dermacryl 79),及各种脂肪族树脂和芳香族树脂。 Non-limiting examples of viscosity enhancers can be used as additional substances • include methyl vinyl ether copolymers with maleic anhydride (the Gantrez polymers), polyethylene glycol and polyvinylpyrrolidone copolymers, gelatin, low molecular weight poly isobutylene rubber, acrylsan group burning / octyl acrylamide (acrylsan alkyl / octylacrylamido) copolymer (Dermacryl 79), and various aliphatic resins and aromatic resins.

[0064] 当用于本发明所述的粘性制剂时,术语“可洗涤的”、“洗涤”或“通过洗涤除去”是指所述粘性制剂通过洗涤溶剂的应用,使用正常或中等量的洗涤力被除去的能力。 [0064] When used in the viscosity of the formulation of the present invention, the term "washable", "washing" or "removed by washing" refers to application of the adhesive formulation by washing solvent, or using a normal amount of washing medium force the ability to be removed. 通过洗涤除去所述制剂所需的力不应该引起明显的皮肤刺激或磨损。 Removed by washing the force required for the formulation should not cause significant skin irritation or abrasion. 一般来说,轻柔的洗涤力伴随适当洗涤溶剂的应用足以去除本文公开的粘性制剂。 In general, application of gentle force accompanied by an appropriate washing solvent washing sufficient to remove the viscous formulations disclosed herein. 可以用于通过洗涤去除本发明所述制剂的溶剂是大量的,但是优选地选自通常可接受的溶剂,包括本文所列的挥发性溶剂。 The solvent may be used in the formulations of the present invention is removed by washing is substantial, but preferably selected from generally acceptable solvents include volatile solvents listed herein. 优选的洗涤溶剂不会明显地刺激人类皮肤并且通常对一般受治疗者是可得到的。 Preferred washing solvents do not significantly stimulate the human skin and, typically, the subject is generally available. 洗涤溶剂的例子包括但不限于水、乙醇、甲醇、异丙醇、丙酮、乙酸乙酯、丙醇或它们的组合。 Examples of washing solvents include, but are not limited to, water, ethanol, methanol, isopropanol, acetone, ethyl acetate, propanol, or a combination thereof. 在本发明的方面中,所述洗涤溶剂可以选自水、乙醇、异丙醇或它们的组合。 In the aspect of the present invention, the washing solvent may be selected from water, ethanol, isopropanol or combinations thereof. 表面活性剂也可以用在一些实施方式中。 Surfactants may also be used in some embodiments.

[0065] 当其涉及“干燥时间”时,可接受的时间长度是指在标准皮肤和环境条件下应用于皮肤以后,并利用标准测试程序,所述制剂形成不散乱的固化表面所耗费的时间。 [0065] When it relates to "drying time" refers to the length of time is acceptable after application to the skin and the skin under standard environmental conditions, using standard test procedures, the formulation does not form a cured surface scattering time spent . 应该注意,在本申请中的词语“干燥时间”不表示挥发性溶剂(一种或多种)完全蒸发所耗费的时间。 It should be noted that, in this application the term "drying time" does not mean the volatile solvent (one or more) time consumed completely evaporated. 相反地,它表示如上文所述形成不散乱的固化表面所耗费的时间。 Instead, it represents not scattered time spent cured surface formed as described above.

[0066] “标准皮肤”被定义为干性、健康的人类皮肤,其表面温度在约30°C到约36°C之间。 [0066] "standard skin" is defined as dry, healthy human skin, its surface temperature between about 30 ° C to about 36 ° C. 标准环境条件由20°C到25°C的温度范围和20%到80%的相对湿度范围加以定义。 It is defined by the standard ambient conditions 20 ° C to the temperature range of 25 ° C and 20% to 80% relative humidity range. 术语“标准皮肤”绝非限制本发明所述制剂可以使用的皮肤类型或皮肤条件。 The term "normal skin" in no way limiting skin type or condition of the skin of the present invention may be used in the formulation. 本发明所述的制剂可用于治疗所有类型的“皮肤”,包括无损的(标准皮肤)、患病皮肤或受损皮肤。 The formulation of the present invention are useful for treating all types of "skin", including lossless (standard skin), skin diseased or damaged skin. 尽管具有不同特征的皮肤条件可以使用本发明所述的制剂进行处理,但是术语“标准皮肤”的使用仅被用作测试本发明各种实施方式的组合物的标准。 Although the condition of the skin may be used with different characteristics of the preparation process of the present invention, the term "normal skin" is used merely as a standard compositions tested various embodiments of the present invention. 实际上,在标准皮肤上表现良好(如固化,提供治疗有效通量等)的制剂在患病或受损皮肤上同样表现良好。 In fact, it performs well in the standard skin (e.g., curing, etc. to provide a therapeutically effective flux) formulation equally well performance in the diseased or damaged skin.

[0067] 所述“标准测试程序”或“标准测试条件”如下:在标准环境条件下向标准皮肤应用大约0. Imm的粘性固化制剂层,并测量干燥时间。 [0067] The "standard test procedures" or "standard test conditions" are as follows: preparation of a cured tack layer of about 0. Imm under standard ambient conditions for dermal application to a standard, and measuring the drying time. 所述干燥时间定义为所述制剂形成不散乱表面,使得所述制剂不会由于粘附在一片以约5到约lOg/cm2之间的压力按压在所述制剂表面5秒的100%棉布上而丢失质量所耗费的时间。 The drying time is defined as the formulation does not form a scattering surface, since such a formulation does not adhere to a pressure between about 5 to about lOg / cm2 is pressed against the surface of the preparation for 5 seconds 100% cotton the loss of quality time spent.

[0068] “固化层”描述了所述挥发性溶剂系统至少一部分蒸发后,粘性固化制剂的固化或干燥层。 After [0068] "solidified layer" system described in at least a portion of the volatile solvent was evaporated, the adhesive layer drying or curing of the curable formulation. 所述固化层保持粘附于皮肤上,并且优选地能够在标准皮肤和环境条件下,在基本上整个应用期间与受治疗者的皮肤保持良好接触。 The solidified layer remains adhered to the skin, and preferably capable, under standard environmental conditions and skin, substantially maintain good contact with the skin of the subject during the entire application. 优选地,所述固化层也显示出足够的拉伸强度,以便其能够在应用结束时以一片或若干大片从皮肤上揭下(与从皮肤上除去时,破碎成许多小片或碎片的、具有弱拉伸强度的层相反)。 Preferably, the cured layer also exhibits sufficient tensile strength so that it can be applied at the end of one or several to a large peeled off from the skin (when removed from the skin, broken into many small pieces or chips, having Instead of the layer of weak tensile strength).

[0069] 如本文所使用,方便起见,多种药物、化合物和/或溶剂可以在共同列表中列出。 [0069] As used herein, for convenience, more drugs, compounds and / or co-solvents may be listed in the list. 然而,这些列表应该被解释为列表中的每个成员都分别被识别为独立且独特的成员。 However, these lists should be construed as each member of the list are, respectively, is recognized as a separate and unique member. 因此,在没有相反指出的情况下,这些列表中没有一个单独的成员应该仅仅基于它们在共同组中的描述而被解释为同一列表中任何其它成员的事实等效物。 Thus, in the absence of the indicated to the contrary, those not on the list should only be a single member in a common group based on their description be interpreted as the fact that the other member of the same list any equivalents thereof.

[0070] 浓度、数量及其它数值数据在本文可以范围形式表示或描述。 [0070] Concentrations, amounts, and other numerical data may be expressed or described herein in a range format. 应该理解,这样的范围形式仅是出于方便和简洁的目的而使用,因此应该灵活解释,不仅包含作为范围极值而明确陈述的数值,也包含该范围内包括的各个数值或的子范围,就好像每个数值和子范围被明确陈述。 It should be understood that such a range format is merely for convenience and brevity, and thus should be interpreted flexibly to include not only the numerical range as the extreme value explicitly stated, but also contains various value or within the range, including sub-ranges, as if each numerical value and sub-range is explicitly stated. 举例来说,“约0. 01到2. Omm”的数值范围应该被理解为不仅包含约0. Olmm到约2. Omm的明确陈述的值,也包括所示范围内的各个数值和子范围。 For example, "about 0.01 to 2. Omm" numerical range should be understood to include not only the explicitly recited values ​​of about 0. Olmm to about 2. Omm, but also include individual values ​​and subranges within the range shown. 因此,包含在这个数值范围内的有各个数值,如0. 5、0. 7和I. 5,以及子范围,如0. 5到I. 7、0. 7到I. 5和I. 0到 Thus, included within this numerical range are individual values ​​such as 0. 5,0. I. 5 and 7, as well as sub-ranges, such as 0.5 to I. 7,0. 7 and I. 0 to I. 5 to

I. 5等。 I. 5 and so on. 这一相同的原理也适用于仅描述一个数值的范围。 This same principle applies to a numerical value range just described. 而且,这样的解释无论所述范围的宽度或描述的特征如何,应该都适用。 Moreover, this explanation regardless of the breadth of the range or the characteristics described how, should apply.

[0071] 考虑到这些定义,据此,用于药物皮肤输送的制剂可以包含药物、溶剂载体和凝固齐U。 [0071] Taking into account these definitions, whereby the pharmaceutical formulation for transdermal delivery can comprise a drug, and solidifying solvent vehicle together U. 所述溶剂载体可以包括具有一种或多种挥发性溶剂的挥发性溶剂系统和具有一种或多种不挥发溶剂的不挥发溶剂系统,其中所述不挥发溶剂系统对所述药物是促通量的,使得所述药物甚至在大部分挥发性溶剂(一种或多种)蒸发后,能够在一段时间内以治疗有效量被输送。 The solvent may include volatile solvent carrier system having one or more volatile solvents and having one or more non-volatile solvent is non-volatile solvent system, wherein the non-volatile solvent system to the drug is facilitation an amount such that the majority of the drug even after the volatile solvent (s) evaporate can be delivered in a therapeutically effective amount over a period of time. 所述制剂可以在至少一种挥发性溶剂蒸发前具有适合应用于皮肤表面的粘度,并且可以被进一步配制,使得当应用于皮肤表面时,在至少一部分挥发性溶剂(一种或多种)蒸发后所述制剂形成固化层,但是在基本上固化后仍继续输送药物。 The formulation may have a viscosity suitable for application to the skin surface prior to the at least one volatile solvent was evaporated, and may further be formulated such that when applied to the skin surface, at least a portion of the volatile solvent (s) evaporated after formulation the solidified layer is formed, it continues to deliver medication after substantially cured. 在某些实施方式中,固化层可以是粘结的,以便它可以以一片或若干大片从皮肤剥离,或者使用溶剂可以从皮肤洗去。 In certain embodiments, the cured layer may be bonded, so that it can be washed one or several large peeled off from the skin or from the skin using a solvent. 尽管如本文所述,许多其它药物可以被使用,在一个具体的实施方式中,所述药物可以是性激素,而在另一个具体实施方式中,所述药物可以是抗疣药物。 Although, as described herein, many other drugs may be used, in a specific embodiment, the drug may be a hormone, and in another embodiment, the anti-wart drug may be a drug.

[0072] 在一个可选的实施方式中,皮肤输送药物到、进入或穿过皮肤的方法可以包括应用制剂到受治疗者的皮肤表面,其中所述制剂包含药物、溶剂载体和凝固剂。 Method [0072] In an alternative embodiment, the delivery of drugs to the skin, into or through the skin may include applying the formulation to a skin surface of a subject, wherein said pharmaceutical formulation comprises, coagulating agent and a solvent carrier. 所述溶剂载体含有包括一种或多种挥发性溶剂的挥发性溶剂系统和对于所述药物而言促通量的不挥发溶剂系统。 The solvent carrier contains a volatile solvent system comprises one or more volatile solvents and nonvolatile solvent system for promoting flux of the drug concerned. 在该实施方式中,所述制剂可以在所述挥发性溶剂系统蒸发之前具有适合应用并粘附于皮肤表面的粘度,并且所述制剂可以被应用,使得在所述挥发性溶剂系统至少部分蒸发后,所述皮肤表面形成粘附于所述皮肤的固化层。 In this embodiment, the formulation may have a volatile solvent system prior to the evaporation of the appropriate application viscosity and adhesion to the skin surface, and the formulation may be applied, such that at least partial evaporation of the volatile solvent system after the skin surface is formed on the solidified layer adhering to the skin. 额外的步骤包括在持续的时间段内,以治疗有效速率从所述固化层向所述受治疗者皮肤输送所述药物,其中所述药物在所述挥发性溶剂系统基本上蒸发后继续被输送。 Additional steps include sustained period of time, at therapeutically effective rates from the solidified layer to the skin of the subject to deliver the medicament, wherein the medicament continues to be conveyed after the system is substantially volatile solvent was evaporated . 在一些实施方式中,所述固化层可以是柔软的或可弯曲的、粘结性、连续固体,并可以通过剥离除去。 In some embodiments, the cured layer may be flexible or bendable, cohesive, continuous solid, and can be removed by peeling. 应用于皮肤上的所述制剂层的厚度,对于给定制剂和期望的药物输送方面的考虑也应该合适。 The thickness of the formulation layer is applied on the skin, for a given formulation considerations and the desired drug delivery aspects should also be suitable. 如果所述层过薄,所述药物的量可能不足以支持在期望的时间长度内持续输送。 If the layer is too thin, the amount of the drug may not be sufficient to support sustained delivery over the desired length of time. 如果所述层过厚,形成所述固化层的不散乱外表面可能耗费过长的时间。 If the layer is too thick, not messy outer surface of the formed cured layer may take too long. 如果所述药物非常有效并且所述固化层具有非常高的拉伸强度,薄至0.01mm的层可能就足够。 If the drug is very effective and the solidified layer has very high tensile strength, a layer as thin as 0.01mm may be sufficient. 如果所述药物具有相对低的效能且所述固化层具有低拉伸强度,厚至2-3_的层可能是理想的。 If the drugs have relatively low potency and the solidified layer has low tensile strength, thick layer to 2-3_ it may be desirable. 因此,对于大多数药物和制剂,合适的厚度可以从约0. Olmm到约3mm,但是更典型地,从约0. 05mm到约1mm。 Thus, for most drugs and formulations appropriate thickness can be from about 0. Olmm to about 3mm, but more typically, from about 0. 05mm to about 1mm.

[0073] 在另一个实施方式中,制备用于皮肤药物输送的制剂的方法可以包括以下步骤:选择适合皮肤输送的药物;选择或配制对选定药物有促通量作用的不挥发溶剂或不挥发溶剂的混合物,选择与所述药物和所述不挥发溶剂相容的凝固剂,选择或配制与所述药物、所述不挥发溶剂和凝固剂相容的挥发性溶剂系统;以及将上述所有成分配制成制剂。 [0073] In another embodiment, the method of preparing the skin preparation for drug delivery may comprise the steps of: selecting a drug suitable for transdermal delivery; selecting or formulating non-volatile solvent is selected to have a pharmaceutical effect or promote the flux evaporation of the solvent mixture, the drug and the selected non-volatile solvent compatible coagulant selected or formulated with said drug, a non-volatile solvent and the volatile solvent system compatible with the coagulating agent; and all of the above formulated to dispense. 所述制剂可以在挥发性溶剂系统蒸发前具有适合应用于皮肤表面的粘度,并且可以应用于皮肤表面,在那里,所述制剂在至少部分所述挥发性溶剂系统蒸发之后形成固化层。 The formulation may have a volatile solvent system prior to evaporation of the appropriate viscosity is applied to the skin surface, and can be applied to the skin surface, where the formulation cured layer is formed after at least a portion of the volatile solvent system evaporated. 在该实施方式中,所述药物在挥发性溶剂系统基本上蒸发后继续以治疗有效速率被输送。 In this embodiment, the drug continues to be delivered at a therapeutically effective rate in the system is substantially volatile solvent was evaporated.

[0074] 而在又一种实施方式中,输送药物的固化层可以包括药物、不挥发溶剂系统和凝固剂。 [0074] In yet another embodiment, the cured layer may include a drug delivery of the drug, non-volatile solvent system and the coagulating agent. 所述不挥发溶剂系统对所述药物是促通量的。 The non-volatile solvent system to the drug is a pro flux. 固化层可以是粘附在身体表面的、柔软的粘结固体,并且在由此向皮肤输送至少部分所述药物的同时,固化层至少基本上没有水和比水更具挥发性的溶剂,例如,当固化层含有不高于10wt%或甚至5wt%的水和比水更具挥发性的溶剂时,所述固化层可以被认为基本上不含水和比水更具挥发性的溶剂。 Cured layer may be adhered to the surface of the body, a soft coherent solid, at the same time and thus conveying at least a portion of the skin to the drug, the cured layer is at least substantially free of water and more volatile solvent than water, e.g. , when cured layer contains not more than 10wt%, or even to 5wt% of water and a solvent more volatile than water, the cured layer may be considered to be substantially free of water and a solvent more volatile than water. 此夕卜,所述固化层对药物也是促通量的。 Bu this evening, the solidified layer is to promote drug flux. 在一种实施方式中,固化层可以具有如此粘结性和弹性,以致其在至少一个方向上可以被拉伸5%,或甚至10%而不断裂、破裂或与所述固化层应用于其上的皮肤分离,和/或可从皮肤上剥离。 In one embodiment, the cured adhesive layer may have such elasticity and such that it can be stretched at least 5% in one direction, or even 10% without breaking or cracking of the solidified layer which is applied the separation of the skin, and / or may be peeled off from the skin.

[0075] 在一些应用中,降低皮肤表面湿气损失可以是期望的,并且含有选定的或配制的疏水不挥发溶剂系统的固化层可以帮助达到这一目标。 [0075] In some applications, reducing the loss of moisture of the skin surface may be desirable, and or hydrophobic formulation containing selected non-volatile solvent system in the solidified layer can help to achieve this goal. 因此,本发明的另一实施方式涉及其固化层能够提供显著包藏效应(定义为降低身体表面的湿气损失至少约20%,优选至少约40% )的固化制剂。 Accordingly, another embodiment of the present invention is directed to cured layer can provide significant absorbing effect (defined as a body surface to reduce moisture loss of at least about 20%, preferably at least about 40%) of the curable formulation.

[0076] 这些实施方式例证了涉及制剂、方法和固化层的本发明,所述固化层的初始形式通常为半固体(包括乳膏、凝胶、糊剂、软膏剂和其它粘性液体),其可以容易地在皮肤上涂布一层,并且可以快速(在标准皮肤和环境条件下,从15秒到约4分钟)到中等快速(在标准皮肤和环境条件下,从约4分钟到约15分钟)转变为用于药物输送的固化层,例如粘结且柔软的固体层。 [0076] These exemplary embodiments of the present invention relates to formulations, methods and cured layer, the initial form of the cured layer is generally semi-solid (including creams, gels, pastes, ointments, and other viscous liquid) which layer can be easily applied to the skin, and can be quickly (under standard environmental conditions of the skin and, from 15 seconds to about 4 minutes) to moderate rapid (under standard environmental conditions and skin, from about 4 minutes to about 15 min) into a solidified layer for drug delivery, for example, the adhesive layer and the soft solid. 所述固化层可以任选地是可剥离的。 The cured layer may optionally be peelable. 由此形成的固化层能够在持续的时间段内,如数小时到数十小时,输送药物到皮肤,进入皮肤,穿过皮肤等,使得大部分的药物输送发生在固化层形成之后。 Cured layer thus formed can be sustained period of time, such as several hours to several tens hours, delivery of drugs to the skin, into the skin, through the skin, etc., so that most of the drug delivery occurs after cured layer is formed.

[0077] 此外,所述固化层通常粘附在皮肤上,但是具有固化的、最小或没有粘性的外表面,其在应用相对不久之后形成并且基本上不转移到或另外弄脏受治疗者穿着的或所述固化层可能不注意地接触的衣物或其它物体。 [0077] Further, the cured layer is usually adhered to the skin, but with a cured, non-tacky, or the minimum outer surface formed shortly after application of opposing and substantially not transferred to or otherwise subject to wear soiled or the cured layer may inadvertently contact with clothing or other objects. 所述固化层也可以被配制,使得其高度柔软且可拉伸,并因此即使在身体运动时皮肤被拉伸的情况下,例如在膝部、手指、肘或其它关节处,其能够维持与皮肤表面的良好接触。 The cured layer may be formulated so that it is soft and highly stretchable, and thus even in the case where the body movement of the skin is stretched, for example, in the knee, finger, elbow, or other joints, which can be maintained good contact with the skin surface. [0078] 在选择各种可用组分时,如药物、挥发性溶剂系统和不挥发溶剂系统的溶剂载体、凝固剂等,可以有各种考虑。 [0078] When the various available components, such as drugs, volatile and non-volatile solvent system solvent system solvent carrier, coagulant, etc., there may be various considerations. 例如,挥发性溶剂系统可以选自本领域已知的药学上或化妆上可接受的溶剂。 For example, the system may be acceptable volatile solvent is selected from solvents known in the art on pharmaceutically or cosmetically. 在本发明的一个实施方式中,挥发性溶剂系统可以包括乙醇、异丙醇、水、二甲醚、二乙醚、丁烷、丙烷、异丁烷、I, I-二氟乙烷、I, I, I, 2-四氟乙烷、1,1,1,2,3,3,3-七氟丙烷、1,1,1,3,3,3-六氟丙烷、乙酸乙酯、丙酮或它们的组合。 In one embodiment of the invention, the volatile solvent system can include ethanol, isopropanol, water, dimethyl ether, diethyl ether, butane, propane, isobutane, I, the I-difluoroethane, I, I, I, 2- tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,3,3,3-hexafluoropropane, ethyl acetate, acetone, or The combination. 在本发明的另一个实施方式中,挥发性溶剂系统可以包括乙酸异戊酯、变性酒精、甲醇、丙醇、异丁烯、戊烷、己烷、氯丁醇、松节油、环五娃氧烧(cytopentasiloxane)、环甲基娃酮、甲基•乙基酮或它们的组合。 In another embodiment of the present invention, the volatile solvent system can include iso-amyl acetate, denatured alcohol, methanol, propanol, isobutene, pentane, hexane, chlorobutanol, turpentine, five baby ring oxygen burning (cytopentasiloxane ), baby cyclic methyl ketone, methyl ethyl ketone, • or a combination thereof. 挥发性溶剂系统可以包括上述实施方式中所述的任何挥发性溶剂的混合物或组合。 The volatile solvent system can include a mixture or combination of any volatile solvents in the above embodiment.

[0079] 此外,这些挥发性溶剂应该被选择为与制剂中其它成分相容。 [0079] In addition, these volatile solvents should be chosen to be compatible with the other ingredients of the formulation. 期望的是,在制剂中使用合适重量百分比的挥发性溶剂(一种或多种)。 Desirably, the volatile solvent used in the formulation of suitable weight percentage (s). 过多的挥发性溶剂系统延长干燥时间,而过少的挥发性溶剂系统使得难以在皮肤上涂布制剂。 Excessive volatile solvent system to extend the drying time, while too little of the volatile solvent system makes difficult to coat on the skin formulation. 对于大多数制剂,挥发性溶剂(一种或多种)的重量百分比可以从约10wt%到约85wt%,从约20wt%到约50wt%,并且在优选的实施方式中,至少20wt%。 For most formulations, the volatile solvent (s) by weight percentage may be from about 10wt% to about 85wt%, from about 20wt% to about 50wt%, and in a preferred embodiment, at least 20wt%.

[0080] 所述挥发性溶剂系统也可以选为与不挥发溶剂、凝固剂、药物及可能存在的任何其它赋形剂相容。 The [0080] system may also preferably volatile solvent and a nonvolatile solvent, coagulating agent, and any other pharmaceutical excipients may be present are compatible. 例如,聚乙烯醇(PVA)在乙醇中不溶。 For example, polyvinylalcohol (PVA) insoluble in ethanol. 因此,可以溶解PVA的挥发性溶剂需要被配制在固化层中。 Thus, the volatile solvent can dissolve PVA needs to be formulated in the cured layer. 例如,水可以溶解PVA并且可被用作固化制剂中的挥发性溶剂;然而,其中水是唯一挥发性溶剂的制剂的干燥时间对某些应用来说可能过长。 For example, water can dissolve PVA and may be used in the curable formulation a volatile solvent; however, the drying time of the formulation wherein the water is the only volatile solvent may be too long for some applications. 因此,第二种挥发性溶剂(如,乙醇)可以被配制进制剂中以降低水的含量但维持足量的水以保持PVA在溶液中,从而降低该制剂的干燥时间。 Thus, a second volatile solvent (e.g., ethanol) may be formulated into the formulation to reduce the water content but maintains a sufficient amount of water to keep the PVA in solution, thereby reducing the drying time of the formulation.

[0081] 所述不挥发溶剂系统也可以选择或配制为与凝固剂、药物、挥发性溶剂和可能存在的任何其它成分相容。 [0081] The non-volatile solvent system can be selected or formulated to be compatible with the coagulating agent, the drug, solvent and any other volatile constituents may be present. 实验后,大多数不挥发溶剂系统与溶剂载体作为一个整体被恰当地调配。 After the experiment, most of the non-volatile solvent system and the solvent vehicle as a whole is properly formulated. 例如,某些药物在分子量为400的聚乙二醇(PEG) (PEG 400,不挥发溶剂)中具有良好的溶解度,但是在甘油(不挥发溶剂)和水(挥发性溶剂)中具有不良的溶解度。 For example, certain drugs in the molecular weight of polyethylene glycol 400 (PEG) (PEG 400, non-volatile solvent) have good solubility, but in glycerol (non-volatile solvent), and water (volatile solvent) has poor solubility. 然而,PEG 400不能有效地溶解聚乙烯醇(PVA),因此与凝固剂PVA单独不是非常相容。 However, PEG 400 can not effectively dissolve the polyvinyl alcohol (PVA), and therefore not very compatible with the single coagulant PVA. 为了溶解足量活性药物并同时使用PVA作为凝固剂,可以配制包含适当比例的PEG 400和甘油(与PVA相容)的不挥发溶剂系统,达到相容性的折衷。 In order to dissolve a sufficient amount of active drug while using PVA as coagulating agent, it may be formulated containing a non-volatile solvent system of PEG 400 and glycerin appropriate proportions (compatible with PVA), to achieve compatibility compromise. 作为相容性的又一个例子,当Span20被调配进含有PVA的制剂中时,观察到不挥发溶剂/凝固剂的不相容性。 As still another example of compatibility, when the formulation is formulated into Span20 PVA-containing observed incompatibility nonvolatile solvent / coagulating agent. 使用这种组合,在挥发性溶剂蒸发后,Span 20可以从制剂中分离出来并在固化层的表面形成油性层。 Using this combination,, Span 20 can be separated after evaporation of volatile solvents from the formulation and is formed out of an oil layer on the surface of the cured layer. 因此,恰当的凝固剂/不挥发溶剂选择在开发可行的制剂方面是期望的。 Thus, appropriate coagulant / nonvolatile solvent selected aspects of developing a viable formulation is desirable.

[0082] 更详细地,可以单独或组合使用以形成不挥发溶剂系统的不挥发溶剂可以选自多种药学上可接受的液体,包括但不限于,在本发明的一种实施方式中,不挥发溶剂系统可以包括甘油、丙二醇、异硬脂酸、油酸、丙二醇、三乙醇胺、氨丁三醇、甘油三乙酸酯、失水山梨糖醇单月桂酸酯、失水山梨糖醇单油酸酯、失水山梨糖醇单棕榈酸酯、丁醇或它们的组合。 [0082] In more detail, may be used alone or in combination to form non-volatile solvent is non-volatile solvent system may be selected from a variety of pharmaceutically acceptable liquids, including but not limited to, in one embodiment of the present invention, not a volatile solvent system can include glycerol, propylene glycol, isostearic acid, oleic acid, propylene glycol, triethanolamine, tromethamine, triacetin, sorbitan monooleate, sorbitan monooleate alcohol esters, sorbitan monopalmitate, butanol, or combinations thereof. 在另一个实施方式中,不挥发溶剂系统可以包括苯甲酸,丁醇,癸二酸二丁酯,甘油二酯,双丙甘醇,丁子香酚,脂肪酸如椰子油、鱼油、棕榈油、葡萄籽油,十四酸异丙酯,矿物油,油醇,维生素E,甘油三酯,失水山梨糖醇脂肪酸酯表面活性剂,柠檬酸三乙酯,或它们的组合。 In another embodiment, the non-volatile solvent system can include benzoic acid, butyl alcohol, dibutyl sebacate, diglycerides, dipropylene glycol, eugenol, fatty acids such as coconut oil, fish oil, palm oil, grape oil, isopropyl myristate, mineral oil, oleyl alcohol, vitamin E, triglycerides, sorbitan fatty acid ester surfactants, triethyl citrate, or combinations thereof. 在进一步的实施方式中,不挥发溶剂系统可以包括1,2,6_己三醇,烷三醇(alkyltriol),烷二醇(alkyldiol),乙酰单甘油酯,生育酹,烧基二氧戍环(alkyl dioxolanes),对丙烯基茴香醚(p-propenylanisole),茴香油,杏仁油,二甲基异山梨醇,烧基葡糖苷,苯甲醇,蜂蜡,苯甲酸苄酯,丁二醇,辛酸/癸酸甘油三酯,焦糖,山扁豆油(cassia oil),蓖麻籽油,肉桂醒,肉桂油(cinnamon oil), 丁香油,椰子油,可可脂,椰子甘油酯(cocoglyceride),香菜油,玉米油,芫荽油,玉米糖浆,棉籽油,甲酚,环甲基硅酮,二醋精,二乙酰单甘油酯(diacetylated monoglyceride) ,二乙醇胺,二甘醇一乙醚,甘油二酯,乙二醇,桉树油,月旨肪,脂肪醇,香料,液体糖,生姜提取物,甘油,高果糖玉米糖浆,氢化蓖麻油,IP棕榈酸酯,柠檬油,白柠檬油,苧烯,牛奶,一醋精, 甘油单酯,肉豆蘧油,辛 In a further embodiment, the non-volatile solvent system can include 1,2,6_ hexanetriol, alkyl triol (alkyltriol), alkanediols (alkyldiol), acetylated monoglycerides, tocopherol sprinkle, burning dioxo Shu cycloalkyl (alkyl dioxolanes), of anethole (p-propenylanisole), anise oil, apricot oil, dimethyl isosorbide, burning glucoside, benzyl alcohol, bees wax, benzyl benzoate, butylene glycol, caprylic acid / capric triglyceride, caramel, mountain flat soybean oil (cassia oil), castor oil, cinnamon awake, cinnamon oil (cinnamon oil), clove oil, coconut oil, cocoa butter, coco-glycerides (eg cocoglyceride), parsley oil, corn oil, coriander oil, corn syrup, cottonseed oil, cresol, cyclomethicone, diacetin, diacetylated monoglyceride (diacetylated monoglyceride), diethanolamine, diethylene glycol monoethyl ether, diglycerides, ethylene glycol, eucalyptus oil, fatty purpose month, fatty alcohols, flavors, liquid sugars ginger extract, glycerin, high fructose corn syrup, hydrogenated castor oil, the IP palmitate, lemon oil, lime oil, limonene, milk , a triacetin, monoglycerides, nutmeg oil Qu, suberic 十二烷醇,橄榄醇(olivealcohol),甜橙油,棕榈油,花生油,PEG植物油,薄荷油,凡士林油,苯酚,松针油,聚丙二醇,芝麻油,留兰香油,大豆油,植物油,植物油制起酥油(vegetable shortening),乙酸乙烯酯,蜡,2-(2-(十八烷氧基)乙氧基)乙醇,苯甲酸苄酯,丁基化羟基苯甲醚,小烛树腊,巴西棕榈腊(carnauba wax),鲸腊硬脂醇聚醚-20 (ceteareth-20),十六烧醇,聚甘油(polyglyceryl), 二聚轻基硬脂酸酯(dipolyhydroxy stearate), PEG-7 氢化蓖麻油,邻苯二甲酸二乙酯,癸二酸二乙酯,二甲基硅氧烷,邻苯二甲酸二甲酯,PEG脂肪酸酯如PEG-硬脂酸酯、PEG-油酸酯、PEG-月硅酸酯,PEG脂肪酸二酯如PEG- 二油酸酯、PEG- 二硬脂酸酸酯、PEG-蓖麻籽油,山嵛酸甘油酯,PEG甘油脂肪酸酯如PEG月桂酸甘油酯、PEG硬脂酸甘油酯、PEG油酸甘油酯,己烯甘油(hexylene glycerol),羊毛脂,月桂酸二 Dodecanol, olive alcohol (olivealcohol), sweet orange oil, palm oil, peanut oil, PEG vegetable oil, peppermint oil, petrolatum, phenol, pine needle oil, polypropylene glycol, sesame oil, spearmint oil, soybean oil, vegetable oil, vegetable oil system shortening (vegetable shortening), vinyl acetate, wax, 2- (2- (octadecyloxy) ethoxy) ethanol, benzyl benzoate, butylated hydroxyanisole, candelilla wax, Brazil palm wax (carnauba wax), cetyl steareth -20 (ceteareth-20), sixteen burning alcohol, polyglycerin (polyglyceryl), dimeric light-yl stearate (dipolyhydroxy stearate), PEG-7 hydrogenated castor oil, diethyl phthalate, diethyl sebacate, dimethicone, dimethyl phthalate, PEG fatty acid esters such as PEG- stearate, PEG- oleate , PEG- month silicate, fatty acid esters such as PEG- PEG dioleate, PEG- acid esters stearate, PEG- castor oil, glyceryl behenate, PEG glycerol fatty acid esters such as lauryl PEG glycerides, PEG glyceryl stearate, PEG glyceryl oleate, glyceryl hexene (hexylene glycerol), lanolin, lauric acid 醇酰胺(lauric diethanolamide),月桂乳酸酯,月桂硫酸酯,亚甲磷酸,甲基丙烯酸,多甾醇提取物(multisterol extract),肉豆蘧醇,中性油,PEG-辛基苯基醚,PEG-烧基醚如PEG-十六烷基醚、PEG-十八烷基醚,PEG-失水山梨糖醇脂肪酸酯如PEG-失水山梨糖醇二异硬脂酸酯、PEG-失水山梨糖醇单硬脂酸酯,丙二醇脂肪酸酯如丙二醇硬脂酸酯、丙二醇,辛酸酯/癸酸酯,吡咯烷酮羧酸钠,山梨醇,三十碳六烯,stear-o-wet,甘油三酯,烷基芳基聚醚醇,失水山梨糖醇醚的聚氧乙烯衍生物,饱和的聚乙二醇化的C8-C10甘油酯(saturated polyglycolyzed C8-C10 glyceride), N-甲基卩比咯烧酮,蜂蜜,聚氧乙基化甘油酯,二甲亚砜,氮酮及相关化合物,二甲基甲酰胺,N-甲基甲酰胺,脂肪酸酯,脂肪醇醚,烷基酰胺(N,N-二甲基烷基酰胺),N-甲基吡咯烷酮相关化合物,油酸乙酯,聚甘油化脂肪酸(poly Alkanolamides (lauric diethanolamide), lauryl lactate, lauryl sulfate, methylenedioxy acid, methacrylic acid, multi-sterol extract (multisterol extract), myristoyl Qu alcohol, neutral oil, PEG- octylphenyl ether, ethers such as PEG- burning PEG- cetyl ether, PEG- stearyl ether, PEG- sorbitan fatty acid esters such as PEG- sorbitan sorbitan diisostearate, PEG- loss water, sorbitan monostearate, propylene glycol fatty acid esters such as propylene glycol stearate, propylene glycol, caprylate / caprate, sodium pyrrolidone carboxylate, sorbitol, squalene, stear-o-wet , polyoxyethylene derivatives of triglycerides, alkylaryl polyether alcohols, sorbitan ethers, saturated polyglycolized glycerides of C8-C10 (saturated polyglycolyzed C8-C10 glyceride), N- methyl Jie-yl ketone burning pyrrole, honey, polyoxyethylated glycerides, dimethyl sulfoxide, azone and related compounds, dimethylformamide, N- methyl formamide, fatty acid esters, fatty alcohol ethers, alkyl amide (N, N- dimethyl-alkylamide), N- methylpyrrolidone related compounds, ethyl oleate, polyglycerol fatty acid (poly glycerized fatty acids),单油酸甘油酯,单肉豆蘧酸甘油酯,脂肪酸的甘油酯,丝氨基酸(silk amino acid), PPG-3苯甲醚肉豆蘧酸酯,二-PPG2肉豆蘧醇聚醚10-己二酸酯(Di_PPG2 myreth 10-adipate), honeyquat,焦谷氨酸钠,海甘蓝油(abyssinica oil),二甲基娃氧烧,澳洲坚果油(macadamia nut oil),绣线菊杆油(limnanthes alba seedoil),鲸蜡硬脂醇,PEG-50牛油树脂,牛油树脂,芦荟汁(aloevera juice),苯基三甲基硅氧烷,水解的小麦蛋白,或它们的组合。 glycerized fatty acids), glyceryl monooleate, glyceryl mono myristoyl Qu, esters of fatty acids, silk amino acids (silk amino acid), PPG-3 anisole myristoyl Qu, di- -PPG2 myristoyl Qu polyether 10- adipate (Di_PPG2 myreth 10-adipate), honeyquat, sodium pyroglutamate, crambe oil (abyssinica oil), dimethyl baby burn oxygen, macadamia nut oil (macadamia nut oil), embroidery wire rod chrysanthemum oil (limnanthes alba seedoil), cetearyl alcohol, PEG-50 shea butter, shea butter, aloe vera juice (aloevera juice), phenyl trimethicone, hydrolyzed wheat protein, or their The combination. 而在又一种实施方式中,不挥发溶剂系统可以包括任意上述实施方式中所述的不挥发溶剂的组合或混合物。 In yet another embodiment, the non-volatile solvent system can include a non-volatile solvent combination or mixture of any of the above embodiments described above.

[0083] 除了这些和其它的考虑,不挥发溶剂系统可以,并且优选地应该也作为本发明制剂中的增塑剂,以便当固化层形成时,该层是柔软的,可拉伸的,和/或另外是“皮肤友好的(skin friendly)”。 [0083] In addition to these and other considerations, non-volatile solvent systems can be, and preferably should also serve as a plasticizer in the formulation of the present invention, when cured to form a layer, the layer is flexible, stretchable, and / or other is "skin friendly (skin friendly)".

[0084] 某些挥发性和/或不挥发溶剂(一种或多种)刺激皮肤,但是用于达到药物期望的溶解性和/或渗透性是理想的。 [0084] Certain volatile and / or nonvolatile soluble solvent (s) to stimulate the skin, but for achieving the desired pharmaceutical and / or permeability are desirable. 同样理想的是加入能够阻止或降低皮肤刺激并且与该制剂相容的化合物。 It is also desirable compound can be added to prevent or reduce skin irritation and are compatible with the formulation. 例如,在挥发性溶剂能够皮肤刺激的制剂中,使用能够降低皮肤刺激的不挥发溶剂是有帮助的。 For example, in a volatile solvent capable of formulation of skin irritation, skin irritation can be reduced using non-volatile solvents is helpful. 已知能够阻止或降低皮肤刺激的溶剂的例子包括但不限于甘油、蜂 Examples of known capable of preventing or reducing skin irritation solvents include, but are not limited to, glycerin, bees

蜜和丙二醇。 Honey and propylene glycol. [0085] 本发明的制剂也可以包含两种或多种不挥发溶剂,它们独立地不能产生与根据某一比例并且通常是实验确定的比例调配在一起时一样高的药物通量。 [0085] The formulations of the invention may also comprise two or more non-volatile solvents, they can not independently produce as high drug flux together according to a ratio scale and are generally determined experimentally formulations. 这些初始非促通量或较不促通量的不挥发溶剂当调配在一起时变得更促通量的一个可能的原因可以是由于药物的电离态被优化到具有更高通量的物理形式,或不挥发溶剂以某一其它的协同形式起作用。 These initial non-pro-pro-less flux or flux nonvolatile solvent when formulated together becomes a more possible reason may be due to the pro-flux drug ionized physical form to be optimized with higher throughput , nonvolatile solvents or act in some other forms of synergistic. 不挥发溶剂混合物的又一个益处是它可优化制剂的PH或制剂层下的皮肤组织以最小化刺激。 Another benefit of a mixture of non-volatile solvents is that it may optimize the formulation or the skin tissues under the PH formulation layer to minimize irritation. 产生可更促通量的不挥发溶剂系统的不挥发溶剂的合适组合的例子包括但不限于异硬脂酸/三乙醇胺、异硬脂酸/ 二异丙胺、油酸/三乙醇胺、和丙二醇/异硬脂酸。 Examples of suitable composition to produce non-volatile solvent is non-volatile solvent system can include more pro-flux, but not limited to, isostearic acid / triethanolamine, isostearic acid / diisopropylamine, oleic acid / triethanolamine, and propylene glycol / isostearic acid.

[0086] 凝固剂的选择也可以考虑该粘性制剂中存在的其它组分进行。 [0086] coagulant may be considered to select the other components of the adhesive will be present in the formulation. 凝固剂可以被选择或配制为与药物和溶剂载体(包括挥发性溶剂(一种或多种)和不挥发溶剂系统)相容,以及在固化层形成时为其提供期望的物理性质。 Coagulant may be selected or formulated with the drug and solvent vehicle (including the volatile solvent (s) and non-volatile solvent system) compatible, and when cured layer is formed to provide the desired physical properties. 取决于药物、溶剂载体和/或可能存在的其它组分,凝固剂可以选自多种试剂。 Depending on the drug, solvent vehicle, and / or other components may be present, the coagulant may be selected from a variety of agents. 在一种实施方式中,凝固剂可以包括分子量(MW)范围是20, 000-70, 000的聚乙烯醇(Amresco),分子量范围是80,000-160,000的聚乙烯甲基醚/马来酐共聚物(ISP Gantrez ES-425和Gantrez ES-225)的酯,分子量范围是120, 000-180, 000的甲基丙烯酸丁酯和甲基丙烯酸甲酯的中性共聚物(Degussa PlastoidB),分子量范围是100,000-200, 000的甲基丙烯酸二甲基氨基乙基酯-甲基丙烯酸丁酯-甲基丙烯酸甲酯共聚物(Degussa Eudragit E100),分子量在5,000以上或与EudragitRLPO(Degussa)相似的丙烯酸乙酯-甲基丙烯酸甲酯-三甲基铵乙基甲基丙烯酸酯氯化物(trimethyIammonioethyI methacrylate chloride)的共聚物,分子量在5,000 以上的玉米醇溶蛋白(Zein)(醇溶谷蛋白(prolamine))如分子量约35,000的玉米醇溶蛋白(Freemanindustries(Freeman 工业)),具有与Instant Pure-Cote B793(Grain ProcessingCorporation)相似分子量的预胶凝淀粉,分子量 In one embodiment, the coagulant may comprise a molecular weight (MW) in the range of 20, 000-70, 000 polyvinyl alcohol (Amresco), molecular weight range of 80,000-160,000 polyvinyl methyl ether / MA esters anhydride copolymer (ISP Gantrez ES-425 and Gantrez ES-225), the molecular weight range 120, 000-180, 000, butyl methacrylate and methyl methacrylate neutral copolymer (Degussa PlastoidB) , a molecular weight in the range of 100,000-200, 000 methacrylate, dimethylaminoethyl acrylate - butyl methacrylate - methyl methacrylate copolymer (Degussa Eudragit E100), or less than 5,000 and EudragitRLPO (Degussa) similar to the ethyl acrylate - methyl methacrylate - trimethylammonium ethyl methacrylate chloride (trimethyIammonioethyI methacrylate chloride) copolymers, zein molecular weight of less than 5,000 (zein ) (prolamine (prolamine)) the molecular weight zein (Freemanindustries (Freeman industries) of about 35,000), having Instant Pure-Cote B793 (Grain ProcessingCorporation) pre-gelatinized starch of similar molecular weight, molecular weight 在5,000以上或分子量与Aqualon EC N7、N10、N14、N22、N50或N100 (Hercules)相似的乙基纤维素,具有分子量20,000-250, 000的鱼胶(Norland Products),明胶,分子量在5,000以上的其它动物来源,分子量在5,000以上或分子量与National Starch and Chemical Dermacryl 79相似的丙烯酸酯/辛基丙烯酰胺共聚物。 With a molecular weight of 5,000 or more Aqualon EC N7, N10, N14, N22, N50, or N100 (Hercules) like ethyl cellulose, having a molecular weight of 20,000-250, 000 fish gelatin (Norland Products), gelatin, in other animal sources molecular weight of 5,000 or more, a molecular weight of less than 5,000 or similar to National Starch and Chemical Dermacryl 79 acrylates / octylacrylamide copolymer.

[0087] 在另一实施方式中,凝固剂可以包括乙基纤维素、羟乙基纤维素、羟甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素、甲基纤维素、聚醚酰胺、玉米淀粉、预胶凝玉米淀粉、聚醚酰胺、虫胶(shellac)、聚乙烯吡咯烷酮、聚异丁烯橡胶、聚醋酸乙烯邻苯二甲酸酯(polyvinyl acetate phthalate)或它们的组合。 [0087] In another embodiment, the coagulant may include ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose , methyl cellulose, polyether amides, corn starch, pregelatinized corn starch, polyether amides, shellac (shellac), polyvinyl pyrrolidone, polyisobutylene rubber, polyvinyl acetate phthalate (polyvinyl acetate phthalate ), or combinations thereof. 在进一步的实施方式中,凝固剂可以包括甲基丙烯酸铵(ammonia methacrylate),角叉菜聚糖,水性乙酸邻苯二甲酸纤维素(cellulose acetate phthalate aqueous)如来自Eastman 的CAPNF,羧基聚亚甲基(carboxy polymethylene),醋酸纤维素(微晶),纤维素聚合物,二乙烯基苯苯乙烯,乙烯乙酸乙烯酯,娃树脂,瓜尔胶,瓜尔松脂(guar rosin),谷蛋白,酪蛋白,酪酸I丐,酪酸铵,酪酸钠,酪酸钾,丙烯酸甲酯,微晶蜡,聚乙烯乙酸酯,PVP乙基纤维素,丙烯酸酯,PEG/PVP,黄原胶,甲娃烧氧基三甲酯(trimethyl siloxysilicate),马来酸/酐共聚物,波拉克林(polacrilin),泊洛沙姆(poloxamer),聚环氧乙烧,聚乳酸/聚L-乳酸(poly glacticacid/poly-l-lactic acid),職类树脂,刺槐豆胶,丙烯酸共聚物,聚氨酯分散体,糊精,聚乙烯醇-聚乙二醇共聚物,甲基丙烯酸-丙烯酸乙酯共聚物如BASF的Kollicoat聚合物,基于甲基丙烯酸和甲基 In a further embodiment, the coagulant may comprise ammonium methacrylate (ammonia methacrylate), carrageenan, cellulose acetate phthalate aqueous (cellulose acetate phthalate aqueous) as the CAPNF from Eastman, carboxy polymethylene group (carboxy polymethylene), cellulose acetate (microcrystalline), cellulose polymers, divinyl benzene styrene, ethylene vinyl acetate, resins baby, guar gum, guar Gilson lipid (guar rosin), gluten, casein protein, I cai butyric acid, ammonium caseinate, sodium caseinate, potassium caseinate, methyl acrylate, microcrystalline wax, polyvinyl acetate, PVP ethyl cellulose, acrylate, PEG / PVP, xanthan gum, A baby burn oxygen group trimethyl (trimethyl siloxysilicate), maleic acid / anhydride copolymer, polacrilin (polacrilin), poloxamers (poloxamer), polyethylene oxide burn, PLA / L- lactic acid (poly glacticacid / poly -l-lactic acid), category resin, locust bean gum, acrylic copolymers, polyurethane dispersions, dextrin, polyvinyl alcohol - polyethylene glycol copolymer, methacrylic acid - ethyl acrylate copolymers such as BASF's Kollicoat polymers based on methacrylic acid and 丙烯酸酯的聚合物如聚(甲基丙烯酸),或它们的组合。 Acrylate polymers such as poly (methacrylic acid), or a combination thereof. 在另一个实施方式中,凝固剂可以包括任何上述实施方式中所述的凝固剂的组合。 In another embodiment, the coagulant may comprise a combination of any of the above described embodiments of the coagulant. 其它聚合物也可能适合作为凝固剂,取决于溶剂载体组分、药物和给定制剂的具体功能要求。 Other polymers may also be suitable as a coagulant, depending on the solvent vehicle components, the drug, and a specific function of a given formulation requirements. 其它聚合物也可能适合作为凝固剂,取决于溶剂载体组分、药物和给定制剂的具体功能要求。 Other polymers may also be suitable as a coagulant, depending on the solvent vehicle components, the drug, and a specific function of a given formulation requirements.

[0088] 在一个实施方式中,不挥发溶剂系统和凝固剂(一种或多种)应该彼此相容。 [0088] In one embodiment, the non-volatile solvent system and the coagulating agent (s) should be compatible with each other. 相容性可以定义为:i)除了通量有些降低外,所述凝固剂对不挥发溶剂系统的功能基本没有不良影响;ii)所述凝固剂可以将不挥发溶剂系统保持在固化层内,以使得不挥发溶剂基本没有渗出该层,和/或iii)利用选定的不挥发溶剂系统和凝固剂形成的固化层具有可接受的柔软度、刚性、拉伸强度、弹性和对皮肤的粘着性。 Compatibility can be defined as: i) In addition to an outer somewhat reduced throughput, the coagulant substantially no adverse effect on the function of the non-volatile solvent system; ii) The coagulant may be maintained non-volatile solvent system in the solidified layer, so that the nonvolatile solvent is substantially free of exudation of the layer, and / or iii) using the selected non-volatile solvent system and the solidified layer formed coagulant having acceptable flexibility, rigidity, tensile strength, and elasticity of the skin adhesion. 不挥发溶剂系统与凝固剂的重量比可以从约0.1 : I到约10 : I。 By weight of non-volatile solvent system and the coagulating agent ratio may be from about 0.1: I to about 10: I. 另一方面,不挥发溶剂系统与凝固剂的重量比可以从约0.2 : I到约4 : I,并且更优选地从约0. 5 : I到约2 : I。 On the other hand, the weight of non-volatile solvent system and the coagulating agent ratio may be from about 0.2: I to about 4: I, and more preferably from about 0. 5: I to about 2: I.

[0089] 固化层——其也任选地是揭片——的柔软度和可拉伸性在一些应用中可以是期望的。 [0089] The solidified layer - which may also optionally exposing sheet - the softness and stretchability in some applications may be desirable. 例如,某些非类固醇抗炎药(NSAID)可被直接应用于关节和肌肉上,以经皮输送至关节或肌肉内。 For example, certain non-steroidal anti-inflammatory drug (NSAID) may be applied directly to the joints and muscles, percutaneously delivered to the joints or intramuscular. 然而,关节和某些肌群上的皮肤区域在身体运动时通常被显著拉伸。 However, joints and muscles on some area of ​​skin is typically significantly stretched during body motion. 这样的运动阻碍不可拉伸贴剂与皮肤维持良好接触。 Such movement obstruction inextensible patches good contact with the skin is maintained. 洗剂、软膏剂、乳膏、凝胶、泡沫、糊剂等由于上述理由可能也不适合使用。 Lotions, ointments, creams, gels, foams, pastes, etc. Due to the above reasons may not be suitable for use. 因此,在NSAID经皮输送入关节和/或肌肉时,本发明的固化制剂可以提供独特的优点和益处。 Accordingly, the NSAID percutaneously delivered into the joints and / or muscles, cured formulations of the invention may offer unique advantages and benefits. 应该指出,尽管良好的可拉伸性在一些应用中可以是期望的,但是本发明的固化制剂并非总是需要是可拉伸的,引文本发明的某些应用不必获益于这一性质。 It should be noted that although good stretchability in some applications it may be desirable, but the cured formulation of the invention does not always need to be stretchable citations certain applications of the present invention is not necessarily benefit from this property. 例如,如果所述制剂应用于一小块面部区域过夜以治疗痤疮,即使固化层是不可拉伸的,受治疗者会经历最小的不适和制剂-皮肤分离,因为面部皮肤在睡眠周期中通常不会被拉伸得非常多。 For example, if the formulation is applied to a small area of ​​the face to treat acne overnight, even when the cured layer is non-stretchable, a subject will experience minimal discomfort and formulations - separated from the skin, since the facial skin is usually not in the sleep cycle It will be stretched very much.

[0090] 依据本发明的实施方式制备的制剂的进一步特征涉及干燥时间。 [0090] According to a further feature relates to the drying time of the formulation prepared according to the present invention. 如果制剂干燥过快,在该制剂固化前用户可能没有足够的时间在皮肤表面将制剂涂布成薄层,导致较差的皮肤接触。 If excessive drying agents, in the formulation prior to curing the user may not have enough time to the surface of the skin the formulation is applied in a thin layer, resulting in poor skin contact. 如果该制剂干燥过慢,受治疗者在恢复可能除去未固化制剂的正常活动(如穿衣)之前不得不长时间等待。 If the formulation is too slow drying, you have a long wait before the subject may be removed to restore normal activity in uncured formulation (e.g., clothing). 因此,理想的是,干燥时间长于约15秒但短于约15分钟,并且优选地从约0. 5分钟到约5分钟。 Accordingly, it is desirable that the drying time is longer than about 15 seconds but shorter than about 15 minutes, and preferably from about 0.5 minutes to about 5 minutes.

[0091] 本发明的固化层的其它益处包括存在可以由材料本身形成的物理屏障。 [0091] Other benefits of the present invention, the cured layer include the presence of a physical barrier may be formed of a material itself. 在一些疾病或损伤情况下,皮肤表面对外界物体的接触敏感或者如果与外界物体接触容易感染。 In some cases the disease or injury, the skin surface contact external objects sensitive or contact with foreign objects, if susceptible. 在那些情况下,固化层可以为皮肤表面提供物理保护。 In those cases, the cured layer may provide physical protection to the skin surface. 例如,局部麻醉剂和诸如可乐定的其它试剂可以被局部输送,以治疗与神经病变相关的疼痛,如糖尿病神经性疼痛。 For example, local anesthetic and other agents such as clonidine may be localized delivery to treat pain associated with neuropathy, such as diabetic neuropathic pain. 由于许多这样的患者感觉到剧痛,甚至是在他们的皮肤仅被轻轻接触也是如此,所以固化层的物理屏障可以防止或最小化由物体或其它无意接触引起的疼痛。 Since many such patients feel pain, even in their contact with the skin is only slightly so, so a physical barrier cured layer can be prevented or minimized by the object or other pain caused by inadvertent contact.

[0092] 这些和其它优点可以被总结在下文的非限制性益处列表中,如下。 [0092] These and other advantages may be summarized in the following non-limiting list of benefits, as described below. 本发明的固化层可以被制备成容易以半固态剂型使用的初始形式。 Cured layer of the present invention may be readily prepared initially in the form of a semi-solid dosage form. 此外,在挥发性溶剂系统蒸发后,应用于皮肤的制剂层相对稠,并能够含有比传统乳膏、凝胶、洗剂、糊剂、软膏剂等的典型层多得多的活性药物,而且能够抵抗无意去除。 Further, after evaporation of the volatile solvent system, the formulation is applied to the skin layer is relatively thick, and can contain the active layer than the typical conventional pharmaceutical creams, gels, lotions, pastes, ointments and the like much more, and resistant to unintentional removal. 所述固化层含有对药物促通量的不挥发溶剂系统,以使药物能够在持续的时间段内以治疗有效速率输送。 The cured layer comprises non-volatile solvent system to promote drug flux, so that the drug can be sustained period of time at a therapeutically effective delivery rate. 而且,由于固化层保持粘附于皮肤并且优选地是可剥离的,可以发生固化层的轻松除去,可以不需要溶剂或表面活性剂的帮助。 Further, since the solidified layer remains adhered to the skin and is preferably peelable cured layer may be removed easily occur, help may not require a surfactant or a solvent. 在一些实施方式中,材料在皮肤上的粘性和弹性使得在高度可拉伸的皮肤区域——如关节和肌肉上——皮肤拉伸时,固化层不会与皮肤分离。 In some embodiments, the viscous and elastic material on the skin at a height such that the stretchable skin area - such as the joints and muscles - the skin is stretched, the cured layer is not separated from the skin. 例如,在一种实施方式中,固化层可以在至少一个方向上被拉伸5%,或甚至10%或更多,而不断裂、破裂和/或与该层应用的皮肤表面分离。 For example, in one embodiment, the cured layer may be stretched in one direction at least 5%, or even 10% or more, without breaking, cracking and / or separation of the skin surface of the layer applied. 此外,固化层可以被配制为有利地输送药物并保护敏感皮肤区域而不断裂或破裂。 Further, the cured layer may advantageously be formulated as a pharmaceutical delivery and protection of sensitive skin area without breaking or rupturing.

[0093] 在本发明的一个实施方式中,固化层在期望的药物输送结束后可以用诸如水或乙醇的溶剂洗去。 [0093] In one embodiment of the present invention, the layer is cured after the desired drug delivery may be a solvent such as water or ethanol wash. 也可以用于洗去固化制剂的其它溶剂包括但不限于本文所列的挥发性溶齐U。 Other solvents may also be used to wash the cured formulation include, but are not limited to those listed herein volatile solvents together U. 通过洗涤而被除去的能力对某些应用特别有利。 Ability to be removed by washing particularly advantageous for certain applications. 例如,如果固化制剂应用于毛发很多的身体区域(如应用在带有阴毛的生殖器皮肤区域的抗生殖器疱疹的固化制剂),通过剥离的去除可能引起不适并因此是不期望的,从而,洗涤在这类应用中可以是优选的去除形式。 For example, if the cured formulation applied to the hair many areas of the body (such as the application of anti-genital skin in the pubic area with the curing agents of genital herpes), removing by peeling may cause discomfort and therefore undesirable, whereby washing such applications may be preferred to remove form. 在另一个例子中,如果固化制剂应用于掌面,如手掌或足底,通过剥离而去除的能力可以是将粘附于皮肤表面的制剂的次要考虑因素。 In another example, if the curable formulation is applied to the palm as the palm or the foot, the ability to be removed by peeling may be adhered to the skin surface of the secondary formulation considerations. 在这些情况下,配制为用水或乙醇容易洗去的固化层可能是更期望的。 In these cases, water or ethanol is formulated readily washed off the cured layer may be more desirable. 在洗涤实施方式中,用于洗去固化层的溶剂可以溶解该层或使其不太粘附于皮肤,以便其能够容易地从皮肤上除去。 Washed embodiment, the solvent used to wash the cured layer can not dissolve the layer or it adhered to the skin, so that it can be easily removed from the skin.

[0094] 进一步注意到,本发明的固化层可以保持不挥发溶剂系统一其对输送所述药物而言被优化——的实质量于皮肤表面是一个独特的特征。 [0094] Further is noted that the cured layer of the present invention can maintain a non-volatile solvent system which is optimized in terms of delivery of the drug - a solid mass is a unique feature of the skin surface. 这一特征能够提供相对于现有产品的独特优势。 This feature can provide unique advantages over existing products. 例如,Penlac是一种广泛用于治疗指甲真菌感染的产品。 For example, Penlac product is widely used to treat fungal nail infections. 它含有药物环吡酮(ciclopirox)、挥发性溶剂(乙酸乙酯和乙酸异丙酯)和聚合物。 It contains a drug ciclopirox (ciclopirox), volatile solvents (ethyl acetate and isopropyl acetate) and the polymer. 在被应用于指甲表面后,挥发性溶剂迅速蒸发并且该制剂层固化成硬漆膜(lacquer)。 After being applied to the nail surface, the volatile solvent quickly evaporates and the formulation cured to a hard film layer (lacquer). 药物分子被固定在硬漆层中并且基本上不可用于输送进指甲中。 The drug molecules are immobilized in the hard lacquer layer and substantially unavailable for delivery into the nail. 结果,认为所述药物的输送不能在长时间内持续。 As a result, the delivery of the drug that can not be sustained for a long time. 结果,在不被任何特定理论限定的情况下,据认为,这是为何尽管被广泛使用,Penlac只有约10%的效率的至少一个原因。 As a result, without being limited to any particular theory, it is believed that this is why despite being widely used, Penlac at least one reason only about 10% efficiency. 相反地,在本发明的固化层中,药物分子在与皮肤表面如皮肤、指甲、粘膜等表面接触的不挥发溶剂系统中是相当可移动的,因此确保了持续输送。 In contrast, the cured layer in the present invention, the drug molecule is relatively movable in a non-volatile solvent system such as surface of the skin, nails, mucous membrane surface in contact with the skin, thus ensuring continuous delivery.

[0095] 可以从本发明的系统、制剂和方法中获益的应用的具体例子如下。 [0095] Specific examples of applications that may benefit from the system, formulations and methods of the present invention is as follows. 在一种实施方式中,包含布比卡因(bupivacaine)、利多卡因或罗哌卡因的固化层可以被配制,用于治疗糖尿病性神经痛和疱疹后神经痛。 In one embodiment, comprising bupivacaine (as bupivacaine), lidocaine or ropivacaine cured layer may be formulated for the treatment of diabetic neuropathic pain, and post-herpetic neuralgia. 可选地,地布卡因(dibucaine)和a-2激动剂如可乐宁,可以被配制进固化制剂中,用于治疗相同的疾病。 Alternatively, dibucaine (dibucaine) and treatment of the same disease a-2 agonists such as clonidine, can be formulated into formulations cured, for. 在另一种实施方式中,视黄酸和过氧苯甲酰可被混合进固化层中,用于治疗痤疮,或可选地,lwt%的氯林可霉素和5wt%的过氧苯甲酰可被混合进固化制剂中,用于治疗痤疮。 In another embodiment, retinoic acid and benzoyl peroxide may be mixed into the cured layer, for the treatment of acne, or alternatively, lwt% of clindamycin and 5wt% of peroxy benzene formyl may be mixed into the curable agent for treating acne. 在另一种实施方式中,可以制备视黄醇固化制剂(OTC),用于治疗皱纹,或者可以制备利多卡因固化制剂,用于治疗背痛。 In another embodiment, the curing may be prepared retinol formulation (the OTC), for the treatment of wrinkles, or may be prepared lidocaine curable formulation for the treatment of back pain. 在另一种实施方式中,可以制备氧化锌固化制剂,用于治疗尿布疹(由固化层提供的抗刺激性尿液和粪便的物理屏障被认为是有益的),或可以制备抗组胺剂固化层,治疗诸如由常春藤毒素引起的过敏性皮疹。 In another embodiment, the zinc oxide cure formulations can be prepared, for treating diaper rash (anti-irritant urine and faeces physical barrier provided by the cured layer is considered to be useful), or may be prepared antihistamine cured layer, such as the treatment of allergic rash caused by a toxin ivy.

[0096] 其它应用包括输送药物治疗某些皮肤病症,如皮炎、牛皮癣、湿疹、皮肤癌、脱发、皱纹,病毒感染,如唇疱疹(cold sore)、生殖器疱疹、带状疱疹等,特别是发生在经皮贴剂可能不实用的关节或肌肉上的那些。 [0096] Other applications include delivering a drug to treat certain skin disorders such as dermatitis, psoriasis, eczema, skin cancer, alopecia, wrinkles, viral infections, such as herpes labialis (cold sore), genital herpes, herpes zoster, occurring in particular those in the transdermal patch may not be practical joints or muscles. 例如,可以配制含有咪喹莫特的固化制剂用于治疗皮肤癌、过早老化的皮肤、光损伤的皮肤、普通疣和生殖器疣、以及光化性角化病。 For example, the skin can be formulated containing imiquimod imidazole curing agents for the treatment of skin cancer, premature aging, skin photodamage, common warts and genital warts, and actinic keratosis. 可以配制含有抗病毒药物如阿昔洛韦(acyclovir)、喷昔洛韦(penciclovir)、泛昔洛韦(famciclovir)、伐昔洛韦(valacyclovir)、类固醇、二十二醇的固化制剂,用于治疗疱疹病毒感染,如面部区域的唇疱疹和生殖器区域的疱疹。 It may be formulated containing antiviral drugs such as acyclovir (acyclovir), penciclovir (penciclovir), famciclovir (famciclovir), valacyclovir (valacyclovir), steroids, behenyl curable formulation for the treatment of herpes viral infections, such as herpes cold sores and genital area of ​​the face area. 可以配制含有非类固醇抗炎药(NSAID)、辣椒素、a -2激动剂和/或神经生长因子的固化制剂,用于治疗软组织损伤和肌肉-骨骼痛,如各种原因的关节和背痛。 It may be formulated containing a non-steroidal anti-inflammatory drug (NSAID), capsaicin, a -2 agonists and / or nerve growth factor-curable formulation for the treatment of soft tissue and muscle injuries - skeletal pain, such as joint and back pain for a variety of reasons . 如上文讨论,在这些皮肤区域上的贴剂通常在持续的时间内不具有良好的接触,特别是对身体上活跃的受治疗者,并且可能引起不适。 As discussed above, these patches on the skin area typically does not have good contact over a sustained period of time, especially for a subject active body, and may cause discomfort. 同样,传统的半固态制剂,诸如乳膏、洗剂、软膏剂等,可能由于溶剂的挥发和/或制剂的无意去除而过早地停止药物输送。 Similarly, the conventional semi-solid formulations, such as creams, lotions, ointments and the like, may be due to volatilization of the solvent and / or inadvertent removal of the formulation and drug delivery is stopped prematurely. 本发明的固化制剂解决了这些类型的输送系统的缺点。 Curable formulations of the invention addresses the shortcomings of these types of delivery systems.

[0097] —种实施方式可需要含有来自α _2拈抗剂类药物的固化层,其被局部地应用以治疗神经性疼痛。 [0097] - embodiments as may be required to contain the cured layer _2 antagonist drugs derived from α, which is applied topically for the treatment of neuropathic pain. α-2激动剂从该制剂中逐渐释放,以在持续的时间内提供疼痛减轻。 α-2 agonist is gradually released from the formulation to provide pain relieve in duration. 该制剂可以在约5分钟后变成粘结的软固体,并在其应用的时间内,通常是数小时到数十小时,保持粘附于身体表面。 The formulation may become about 5 minutes after bonding soft solids, and their application time, usually several hours to several tens of hours, remain adhered to the body surface. 该固化层在预期使用后容易被除去而不在皮肤表面留下残留制剂。 The cured layer is easily removed without leaving residual formulation on the skin surface upon the intended use.

[0098] 另一实施方式包括含有辣椒素的固化制剂,其可以局部地应用以治疗神经性疼痛。 [0098] Another embodiment comprises a curable formulation comprising capsaicin, which can be applied topically to treat neuropathic pain. 所述辣椒素从该制剂中逐渐释放,以在持续的时间内治疗该疼痛。 The capsaicin is gradually released from the formulation, to treat the pain over a sustained period of time. 该制剂可以在约5分钟后变成粘结的软固体,并在其应用的时间内保持粘附于身体表面。 The adhesive formulation may become a soft solid in about 5 minutes, and remain adhered to the body surface within the time of its application. 所述制剂在干燥后的任何时间容易被除去而不在皮肤表面留下残留制剂。 The formulation is easily removed without leaving residual formulation on the skin surface at any time after drying.

[0099] 另一实施方式包括含有丙酸氯倍他索的固化制剂,其可以局部地应用以治疗手部皮炎。 [0099] Another embodiment comprises a curable formulation comprising clobetasol propionate, which may be applied topically to treat hand dermatitis. 所述丙酸氯倍他索从该制剂中逐渐释放,以在持续的时间内治疗皮炎。 The clobetasol propionate is gradually released from the formulation for the treatment of dermatitis in duration. 该制剂可以在约7分钟后变成粘结的软固体,并在其应用的时间内保持粘附于身体表面。 The adhesive formulation may become a soft solid in about 7 minutes, and remain adhered to the body surface within the time of its application. 物理屏障也保护受损皮肤免受潜在的有害物质损害。 Impaired physical barrier also protects the skin from potentially harmful material damage. 所述制剂在干燥后的任何时间容易被除去而不在皮肤表面留下残留制剂。 The formulation is easily removed without leaving residual formulation on the skin surface at any time after drying.

[0100] 另一实施方式包括含有丙酸氯倍他索的固化制剂,其可以局部地应用以治疗脱发。 [0100] Another embodiment comprises a curable formulation comprising clobetasol propionate, which may be applied topically to treat hair loss. 所述丙酸氯倍他索从该制剂中逐渐释放,以在持续的时间内促进毛发生长。 The clobetasol propionate is gradually released from the formulation to promote hair growth over a sustained period of time. 该制剂可以在约5分钟后变成粘结的软固体,并在其应用的时间内保持粘附于身体表面。 The adhesive formulation may become a soft solid in about 5 minutes, and remain adhered to the body surface within the time of its application. 在干燥后的任何时间,通过剥离以淋浴,所述制剂容易被除去。 At any time after drying, the formulation is easily removed by peeling to shower.

[0101] 另一实施方式包括含有他扎罗汀(tazorac)的固化制剂,用于治疗妊娠纹、皱纹、皮脂腺增生或脂溢性角化病。 [0101] Another embodiment comprises a curable formulation comprising tazarotene (Tazorac), for treating stretch marks, wrinkles, sebaceous hyperplasia or seborrheic keratosis.

[0102] 在另一个实施方式中,可以制备含有甘油的固化制剂,以提供指尖裂缝的保护屏障。 [0102] In another embodiment, the cured formulation may be prepared containing glycerol, in order to provide a barrier to protect the finger crack.

[0103] 仍另一个实施方式可以包括含有选自局部麻醉类如利多卡因和罗哌卡因等,或DSAID类如酮洛芬、卩比罗昔康(piroxicam)、双氯芬酸、却甲新(indomethacin)等药物的固化制剂,其被局部地应用,以治疗背痛、肌肉紧张、或肌筋膜痛或它们的组合的症状。 [0103] yet another embodiment may include a local anesthetic selected from the group comprising hydrocarbons such as lidocaine and ropivacaine the like, or hydrocarbons such as DSAID ketoprofen, piroxicam Jie ratio (as piroxicam), diclofenac, but A new (indomethacin) curing agents and other drugs which are applied topically to treat back pain, muscle tension, myofascial pain or symptoms or a combination thereof. 所述局部麻醉剂和/或NSAID从该制剂中逐渐释放,以在持续的时间内提供疼痛减轻。 The local anesthetic agent and / or an NSAID is gradually released from the formulation to provide pain relieve in duration. 该制剂可以在约5-10分钟后变成粘结的软固体,并在其应用的时间内保持粘附于身体表面。 The adhesive formulation may become a soft solid in about 5-10 minutes, and remain adhered to the body surface within the time of its application. 所述制剂在干燥后的任何时间容易被除去而不在皮肤表面留下残留制剂。 The formulation is easily removed without leaving residual formulation on the skin surface at any time after drying.

[0104] 进一步的实施方式可以包括含有至少一种α-2激动剂、至少一种三环抗抑郁药和/或至少一种局部麻醉药的固化制剂,其被局部地应用以治疗神经性疼痛。 [0104] Further embodiments may include those containing at least one α-2 agonist, at least one tricyclic antidepressant and / or at least one topical anesthetics curable formulation, which is applied topically to treat neuropathic pain . 所述药物(一种或多种)从该制剂中逐渐释放,以在持续的时间内提供疼痛减轻。 Of the drug (one or more) is gradually released from the formulation to provide pain relieve in duration. 该制剂可以在约2-10分钟后变成粘结的软固体,并在其应用的时间内保持粘附于身体表面。 The adhesive formulation may become a soft solid in about 2-10 minutes, and remain adhered to the body surface within the time of its application. 该制剂在干燥后的任何时间容易被除去而不在皮肤表面留下残留制剂。 The formulation is easily removed without leaving residual formulation on the skin surface at any time after drying.

[0105] 一个相似的实施方式可以包括含有药物辣椒素和局部麻醉药的固化制剂,其被局部地应用于皮肤,以提供疼痛减轻。 [0105] A similar embodiment may include a curing formulation containing capsaicin and local anesthetic drugs that are topically applied to the skin to provide pain relief. 另一个实施方式可以包括含有局部麻醉剂和NSAID组合的固化制剂。 Another embodiment may include a curing formulation containing a local anesthetic and a NSAID in combination. 在上述两种实施方式中,所述药物从该制剂中逐渐释放,以在持续的时间内提供疼痛减轻。 In the above two embodiments, the drug is gradually released from the formulation to provide pain relieve in duration. 该制剂可以在约2-10分钟后变成粘结的软固体,并在其应用的时间内保持粘附于身体表面。 The adhesive formulation may become a soft solid in about 2-10 minutes, and remain adhered to the body surface within the time of its application. 该制剂在干燥后的任何时间容易被除去而不在皮肤表面留下残留制剂。 The formulation is easily removed without leaving residual formulation on the skin surface at any time after drying.

[0106] 在另一实施方式中,输送治疗涉及关节和肌肉疾病的病因或症状的药物的固化制剂也可以从本发明的系统、制剂和方法中获益。 [0106] In another embodiment, the curing treatment of the cause or symptoms of the formulation relates to the delivery joint and muscular disease drugs may benefit from the system, formulations and methods of the present invention. 可适用的这类疾病包括但不限于骨关节炎(OA)、风湿性关节炎(RA)、各种其它原因的关节或骨骼痛、肌筋膜痛、肌肉疼痛和运动损伤。 Such diseases applicable include but are not limited to osteoarthritis (OA), rheumatoid arthritis (RA), various joints or other reasons skeletal pain, myofascial pain, muscular pain, and sports injuries. 可以用于这些应用的药物或药物类包括但不限于非类固醇抗炎药(NSAID)如酮洛芬和双氯酚酸、C0X-2选择性NSAID和药剂、C0X-3选择性NSAID和药剂,局部麻醉剂如利多卡因、布比卡因、罗哌卡因和丁卡因,类固醇如地塞米松。 Drug or drug class may be used for these applications include, but are not limited to non-steroidal anti-inflammatory drug (NSAID) such as diclofenac and ketoprofen, C0X-2 selective NSAID and a medicament, C0X-3 and selective NSAID agents, local anesthetics such as lidocaine, bupivacaine, tetracaine, and ropivacaine, steroids such as dexamethasone.

[0107] 输送用于痤疮和其它皮肤病症治疗的药物也可以从本发明的原理中受益,特别是当输送具有较低的皮肤渗透性的药物时。 [0107] for transport of acne and other skin conditions therapeutic drugs may also benefit from the principles of the invention, particularly when the drug has low skin permeability delivery time. 目前,用于治疗痤疮的局部类视黄醇、过氧化物和抗生素大多数以传统半固态凝胶或乳膏进行应用。 Currently, topical retinoids, peroxides and antibiotics for the treatment of acne most conventional semi-solid gel or a cream for application. 然而,由于上述缺点,多个小时的持续输送是不可能的。 However, since the above disadvantages, a plurality of hours of continuous delivery is not possible. 例如,氯林可霉素、过氧苯甲酰和红霉素仅当足量被输送到毛囊时才可以是有效的。 For example, clindamycin, erythromycin, benzoyl peroxide, and only when a sufficient amount is delivered to the hair follicle may be effective. 然而,传统半固体制剂,如畅销的痤疮药物benzaclin凝胶(克林霉素-过氧苯甲酰凝胶剂),通常在其应用后的数分钟内失去其大部分溶剂(在benzaclin的情况下是水)。 However, the conventional semi-solid formulations, such as selling acne medication benzaclin gel (clindamycin - benzoyl peroxide gels), typically losing most of the solvent (in the case of benzaclin within minutes of its application under water). 这短短的几分钟时间可能对药物的持续输送有实质性的损害。 This is just a few minutes could have substantial damage sustained drug delivery. 本发明的制剂通常不具有该局限性。 Formulations of the invention generally do not have this limitation.

[0108] 在另一个实施方式中,治疗神经性疼痛的药物的输送也可以得益于本发明的方法、系统和制剂。 [0108] In another embodiment, the delivery of the drug treatment of neuropathic pain may also benefit from the method of the present invention, systems and formulations. 含有局部麻醉剂如Lidoderm™的贴剂被广泛用于治疗神经性疼痛,如疱疹后神经痛引起的疼痛。 Containing a local anesthetic such as Lidoderm ™ patch it is widely used to treat neuropathic pain, such as pain caused by post-herpetic neuralgia. 由于上面讨论的贴剂的局限性,根据本发明制备的固化层提供了一些独特的好处,以及提供了贴剂使用的一种潜在较为便宜的替代选择。 Due to the limitations discussed above patch, to provide a cured layer produced in accordance with the present invention, a number of unique benefits as well as providing a potentially less expensive alternative to the use of a patch. 为这些应用输送的可能的药物包括但不限于局部麻醉剂如利多卡因、丙胺卡因(prilocaine)、丁卡因、布比卡因、依替卡因;和其它药物,包括辣椒素,α-2激动剂如可乐宁,分离麻醉剂如氯胺酮,三环抗抑郁药如阿米替林。 Possible drug for the delivery of these applications include but are not limited to local anesthetics such as lidocaine, prilocaine (prilocaine), tetracaine, bupivacaine, etidocaine; and other drugs, including capsaicin, alpha] 2 agonists such as clonidine, separating anesthetics such as ketamine, tricyclic antidepressants such as amitriptyline.

[0109] 本发明的固化制剂可以被配制来治疗多种病症和疾病,如肌肉骨骼痛,神经性疼痛,脱发,皮肤疾病,包括皮炎和牛皮癣、以及皮肤修复(护肤处理),和感染,包括病毒、细菌和真菌感染。 [0109] The curable formulations of the invention may be formulated to treat a variety of disorders and diseases, such as musculoskeletal pain, neuropathic pain, hair loss, skin diseases, including psoriasis and dermatitis, and skin repair (skin treatment), and infections, including viral, bacterial and fungal infections. 这样,所述制剂可以输送大量各种类型的药物及活性剂。 Thus, the formulation may be delivered from many types of drugs and agents. 在一种实施方式中,固化制剂可以被配制为包括阿昔洛韦、益康唑、咪康唑、特比萘芬、利多卡因、布比卡因、罗哌卡因、和丁卡因,阿米替林、酮色林、倍他米松二丙酸酯(betamethasonedipropionate)、曲安奈德(triamcinolone acetonide)、氯林可霉素、过氧苯甲酰、维甲酸、异维甲酸、丙酸氯倍他索、卤倍他索丙酸酯、酮洛芬、吡罗昔康、双氯芬酸、茚甲新、咪喹莫特、水杨酸、苯甲酸或它们的组合。 In one embodiment, the curable formulation can be formulated to include acyclovir, econazole, miconazole, terbinafine, lidocaine, bupivacaine, ropivacaine, tetracaine and , amitriptyline, ketanserin, betamethasone dipropionate (betamethasonedipropionate), triamcinolone acetonide (triamcinolone acetonide), clindamycin, benzoyl peroxide, tretinoin, isotretinoin, propionic acid clobetasol, halobetasol propionate, ketoprofen, piroxicam, diclofenac, indomethacin, imiquimod, salicylic acid, benzoic acid, or combinations thereof.

[0110] 在一种实施方式中,所述制剂可以包括抗真菌药物,如阿莫罗芬、布替萘芬、萘替芬、特比萘芬、氟康唑、伊曲康唑、酮康唑、泊沙康唑、雷夫康唑(ravuconazoIe)、伏立康唑、克霉唑、布康唑、益康唑、咪康唑、奥昔康唑、硫康唑、特康唑、噻康唑、卡泊芬净、米卡芬净、阿尼芬净、两性霉素B、AmB、制霉菌素、匹马菌素、灰黄霉素、环吡酮胺、卤丙炔氧苯、托萘酯、和i^一碳烯酸盐,或它们的组合。 [0110] In one embodiment, the formulation may include antifungal agents, such as amorolfine, butenafine, naftifine, terbinafine, fluconazole, itraconazole, ketoconazole , posaconazole, ravuconazole (ravuconazoIe), voriconazole, clotrimazole, butoconazole, econazole, miconazole, oxiconazole, sulconazole, terconazole, tioconazole, caspofungin, micafungin, anidulafungin, amphotericin B, AmB, nystatin, pimaricin, griseofulvin, ciclopirox olamine, halo propynyl oxybenzone, tolnaftate , and i ^ a carbon acid salt, or combinations thereof.

[0111] 在另一实施方式中,所述制剂可以包括抗真菌药物,如阿昔洛韦、喷昔洛韦、泛昔洛韦、万乃洛韦、二十二醇、三氟尿苷、疱疹净、西多福韦、更昔洛韦、普达非洛(podofilox)、鬼臼毒素、利巴韦林、阿巴卡韦、地拉韦啶、地达诺新、依法韦仑、拉米夫定、奈韦拉平、司他夫定、扎西他滨、齐多夫定、安瑞那韦、茚地那韦、奈非那韦、利托那韦、沙奎那韦、金刚烷胺、干扰素、奥司他韦、利巴韦林、金刚乙胺、扎那米韦,或它们的组合。 [0111] In another embodiment, the formulation may include antifungal agents, such as acyclovir, penciclovir, famciclovir, valacyclovir, docosanol, trifluridine, idoxuridine, cidofovir, ganciclovir, podofilox (podofilox), podophyllotoxin, ribavirin, abacavir, delavirdine, didanosine, efavirenz, lamivudine , nevirapine, stavudine, zalcitabine, zidovudine, amprenavir, indinavir, nelfinavir, ritonavir, saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine, zanamivir, or a combination thereof.

[0112] 当所述制剂意欲提供抗菌治疗,其可以被配制,以包含抗菌药物,如红霉素、氯林可霉素、四环素、枯草杆菌肽、新霉素、莫匹罗星、多粘菌素B、喹诺酮类如环丙沙星(ciproflaxin)、或它们的组合。 [0112] When the formulation is intended to provide antimicrobial therapy, which may be formulated to contain antibiotics, such as erythromycin, clindamycin, tetracycline, bacitracin, neomycin, mupirocin, polymyxa polymyxin B, quinolones such as ciprofloxacin (ciproflaxin), or combinations thereof.

[0113] 当所述制剂意欲缓解疼痛,特别是神经性疼痛,该制剂可以包括局部麻醉剂如利多卡因、布比卡因和丁卡因;α-2激动剂,如可乐定。 [0113] When the formulation is intended to relieve pain, particularly neuropathic pain, the formulation may include a local anesthetic such as lidocaine, bupivacaine, and tetracaine; α-2 agonists, such as clonidine. 当所述制剂意欲治疗与发炎相关的疼痛时,其可以被配制为含有非类固醇抗炎药如酮洛芬、吡罗昔康、双氯芬酸、茚甲新、COX抑制剂、普通COX抑制剂、C0X-2选择性抑制剂、C0X-3选择性抑制剂、或它们的组合。 When the formulation for treating related inflammatory intended to pain, which can be formulated to contain a non-steroidal anti-inflammatory drugs such as ketoprofen, piroxicam, diclofenac, indomethacin, COX inhibitors, common COX inhibitors, C0X-2 selective inhibitors, C0X-3 selective inhibitor, or combinations thereof.

[0114] 在另一实施方式中,通过包含活性剂,例如抗痤疮药物如氯林可霉素和过氧苯甲酰、视黄醇、维生素A衍生物如他扎罗汀和异维甲酸、环孢菌素、蒽林、维生素D3、胆钙化醇、隹丐三醇、卡泊三醇、他卡西醇、卡泊三烯(calcipotriene)等,所述制剂可以被配制来治疗皮肤疾病或斑点。 [0114] In another embodiment, the active agent contained by, for example, anti-acne drugs such as clindamycin and benzoyl peroxide, retinol, vitamin A derivatives such as tazarotene and isotretinoin, cyclosporine, anthralin, vitamin D3, cholecalciferol, short-tailed cai triols, calcipotriol, tacalcitol, calcipotriene (calcipotriene) and the like, the formulation may be formulated for treatment of skin disorders or spot.

[0115] 而在另一种实施方式中,治疗疣和其它皮肤病症的药物的输送也将得益于长时间的持续药物输送。 [0115] In yet another embodiment, the delivery treatment of warts and other skin conditions would also benefit from drugs for sustained drug delivery over time. 抗疣化合物的例子包括但不限于:咪喹莫特,雷西莫特,角质层分离剂:水杨酸、ct -轻基酸、硫磺、间苯二酹(rescorcinol)、尿素、过氧苯甲酰、尿囊素、维甲酸、三氯乙酸、乳酸、苯甲酸,或它们的组合。 Examples of anti-wart compound include, but are not limited to: imiquimod, resiquimod, keratolytic agent: salicylic acid, ct - mild acid, sulfur, isophthalic sprinkle (Rescorcinol), urea, peroxy benzene formyl, allantoin, retinoic acid, trichloroacetic acid, lactic acid, benzoic acid, or combinations thereof.

[0116] 进一步的实施方式涉及输送性留体的固化制剂的使用,所述性留体包括但不限于结合孕激素类(progestagen),其由孕酮、炔诺酮、醋酸炔诺酮、去氧孕烯、屈螺酮、双醋炔诺醇、诺孕曲明(norelgestromin)、诺孕酯、左炔诺孕酮、dl_甲基炔诺酮(dl-norgestrel)、醋酸环丙氯地孕酮(cyproterone acetate)、地屈孕酮、醋酸甲轻孕酮、醋酸氯地孕酮、甲地孕酮、普美孕酮、炔诺酮、利奈孕酮、孕二烯酮(gestodene)、7_甲异炔诺酮(tibolene)组成,雄激素类,其由睾酮、甲基睾丸素、氧雄龙、雄留烯二酮、二氢睾酮组成,雌激素类,其由雌二醇、乙炔雌二醇、雌激素、雌酮、结合雌激素、酯化雌激素、哌嗪雌酮硫酯(estropipate),或它们的组合。 [0116] A further embodiment relates to curable agent transporting body using left, leaving the body of binding include, without limitation, progestins (progestagen), consisting of progesterone, norethindrone, norethindrone acetate, to oxygen desogestrel, drospirenone, ethynodiol diacetate, norgestimate sibutramine (norelgestromin), norgestimate, levonorgestrel, norgestrel DL_ (dl-norgestrel), cyproterone acetate chlormadinone progesterone (cyproterone acetate), dydrogesterone acetate A light progesterone, chlormadinone acetate, megestrol, promegestone, norethindrone, lynestrenol, gestodene (gestodene), 7_ a norethynodrel (tibolene) composed of androgens, which is left by testosterone, methyl testosterone, oxandrolone, androstenedione, dihydrotestosterone composition, estrogen, which is estradiol, ethinyl estradiol, estrogen, estrone, conjugated estrogens, esterified estrogens, piperazine estrone thioester (estropipate), or combinations thereof.

[0117] 非性留体也可以使用本发明的制剂输送。 [0117] Non-steroidal exemplary delivery formulations may be used according to the invention. 这些类固醇的例子包括但不限于二丙酸倍他米松、卤倍他索丙酸酯、二醋酸二氟拉松、曲安奈德、地塞米松、醋酸氟轻松(fluocinonide)、哈西奈德、糠酸莫米松、戊酸倍他米松、醋酸氟轻松、氟替卡松丙酸酯、曲安奈德、氟轻松、氟轻可舒松(fIurandrenolide)、地奈德、氢化可的松丁酸酯、氢化可的松戍酸酯、二丙酸阿氯米松、氟米松pivolate (f lumethasone pivolate)、氢化可的松、氢化可的松醋酸酯,或它们的组合。 Examples of such steroids include, but are not limited to, betamethasone dipropionate, halobetasol propionate, diflorasone diacetate, triamcinolone acetonide, dexamethasone, fluocinolone (Fluocinonide), halcinonide, mometasone furoate, betamethasone valerate, fluocinolone acetonide, fluticasone propionate, triamcinolone acetonide, fluocinolone acetonide can fluoro light (fIurandrenolide), desonide, hydrocortisone butyrate, hydrocortisone Shu loose esters, alclometasone dipropionate, flumethasone pivolate (f lumethasone pivolate), hydrocortisone, hydrocortisone acetate, or combinations thereof.

[0118] 进一步的实施方式包括尼古丁的受控输送,用于治疗吸烟者和对尼古丁上瘾的人群的尼古丁依赖。 [0118] Further embodiments include the controlled delivery of nicotine, nicotine treatment for smokers and people addicted to nicotine dependence. 本发明的制剂是经皮输送治疗量的尼古丁的一种成本有效的方式。 Formulations of the present invention is a cost-nicotine transdermal delivery of a therapeutic amount effective manner.

[0119] 另一种实施方式涉及使用所述制剂输送抗组胺药,如苯海拉明和苄吡二胺。 [0119] Another embodiment involves the use of the formulation delivery antihistamines, such as diphenhydramine and benzyl pyrazol-diamine. 这些药剂通过阻断引起发痒的组胺减轻瘙痒,并且也通过提供局部止痛而提供缓解。 These agents by blocking the histamine induced itch relieve itching, and also by providing a topical analgesic and provide relief.

[0120] 可以使用本发明的固化制剂输送的其它药物包括但不限于三环抗抑郁剂,如阿米替林;抗痉挛药,如酰胺咪嗪和阿普唑仑;N-甲基-D-天冬氨酸(NMDA)拈抗剂,如氯胺酮;5-HT2A受体拈抗剂,如酮色林;以及免疫调节剂,如他克莫司和皮克莫司(picrolimus)。 [0120] Other drugs may be cured using the formulations of the invention include, but are not limited to delivery tricyclic antidepressants, such as amitriptyline; anticonvulsants, such as carbamazepine and alprazolam; N-methyl -D - aspartate (NMDA) antagonists, such as ketamine; 5-HT2A receptor antagonists such as ketanserin; and immunomodulatory agents, such as tacrolimus and Pike Mo Division (picrolimus). [0121] 进一步的实施方式包括以下步骤:选择皮肤输送的药物,选择或配制用于所选药物的促通量或高促通量的不挥发溶剂系统,选择与所述不挥发溶剂系统和挥发性溶剂系统相容的凝固剂,选择达到优选的干燥时巾贞(drying time frame)并且与上述成分相容的挥发性溶剂系统,以及将上述成分配制成固化制剂,其可以任选地进一步包括其它成分,如粘度改进剂(一种或多种)、PH改性剂(一种或多种)和软化剂。 [0121] A further embodiment comprises the steps of: selecting a drug delivery skin, or formulated for selected drugs or pro flux selected non-volatile solvent system to promote high throughput, selecting the nonvolatile and volatile solvent system solvent system compatible coagulant, preferably selected reached towel drying Chen (drying time frame) and the volatile solvent system compatible with the above-described components, as well as the above to dispense a cured formulation, which can optionally be further It includes other ingredients, such as viscosity modifier (s), the PH modifier (s) and the softener.

[0122] 另一实施方式涉及在人类皮肤(包括粘膜或指甲表面)上维持促液体通量或高促液体通量的不挥发溶剂,以输送药物进入所述表面下的组织的方法,其包括选择用于皮肤输送的药物,选择或配制用于所选药物的促通量或高促通量的不挥发溶剂系统,选择与所述促通量或高促通量的不挥发溶剂系统和挥发性溶剂系统相容的凝固剂,以及将上述成分配制成固化制剂。 [0122] Another embodiment relates to non-volatile solvent on a human skin (including mucosal or nail surface) maintained a high pro-pro-liquid or liquid flux in the flux, to deliver a drug into a tissue of the lower surface, comprising selected for transdermal delivery of the drug, or formulated for selected non-volatile solvent system to promote non-volatile solvent system selected drug flux or high throughput promoting, select the high-pro or pro-flux and flux volatiles solvent system compatible with the coagulant, and the above to dispense a cured formulation.

[0123] 另一实施方式涉及在人类皮肤(包括粘膜或指甲表面)上保持促液体通量的不挥发溶剂,以输送药物进入人类皮肤或人类皮肤表面下的组织的方法。 [0123] Another embodiment relates to human skin (including mucosal or nail surface) remains pro nonvolatile solvent liquid flux, to deliver a drug into a tissue of the human skin or human skin surface. 该方法包括向人类皮肤应用一层制剂,该制剂包括药物、促通量不挥发溶剂系统、能够使所述促液体通量的不挥发溶剂系统胶凝成软固体的凝固剂、和与所述制剂的其它成分相容的挥发性溶剂系统。 The method comprises applying a layer of formulation to human skin, the formulation comprising a medicament, a non-volatile solvent system to promote the flux, enable the non-volatile solvent system to promote gelling coagulant liquid flux soft solids, and the other volatile components of the solvent system compatible with the formulation. 该制剂层使得至少一些挥发性溶剂系统的蒸发将该制剂从初始的不够固态转化为软的粘结固体层。 This formulation was evaporated layer such that at least some of the volatile solvent system of the formulation is not from the initial solid to a soft coherent solid layer. 在该软的粘结固体层中的药物以治疗有效速率被输送一段持续的时间。 In the soft coherent solid layer of the drug is delivered at a therapeutically effective rate over a sustained period of time.

[0124] 本发明的一个用途可以是用于性激素的输送。 [0124] One use of the present invention may be used for delivery of sex hormones. 在一种实施方式中,用于性激素皮肤输送的制剂可以包括性激素、溶剂载体和凝固剂,该凝固剂在所述挥发性溶剂系统至少部分蒸发后有助于应用一层在皮肤表面上的制剂的固化。 In one embodiment, the hormone formulation for transdermal delivery may include sex hormones, coagulating agent and a solvent carrier, application of a layer of the formulation on the skin surface helps the coagulant after at least partial evaporation of the volatile solvent system It cured. 所述溶剂载体可以包括含有至少一种挥发性溶剂的挥发性溶剂系统,和含有至少一种不挥发溶剂的不挥发溶剂系统。 The solvent carrier may comprise a volatile solvent system comprising at least one volatile solvent, and containing at least one non-volatile solvent is non-volatile solvent system. 所述制剂可以具有适合应用并且在挥发性溶剂系统蒸发前粘附于皮肤表面的粘度。 The formulation may be suitable for use with a volatile solvent system and prior to evaporation of the viscosity adhered to the skin surface. 当应用于皮肤表面时,该制剂在挥发性溶剂系统至少部分蒸发后形成固化层。 When applied to the skin surface, the formulation is formed at least partially cured layer after evaporation of the volatile solvent system. 甚至在挥发性溶剂系统至少基本蒸发后,性激素持续以治疗上充足的速率被输送。 Even after the volatile solvent system is at least substantially evaporated hormone is transported continuously at a sufficient rate of treatment.

[0125] 本发明的制剂也可以用于疣的治疗和消除。 Formulation [0125] The present invention may also be useful in the treatment and elimination of warts. 抗疣制剂可以包括抗疣药物、溶剂载体和凝固剂。 Anti-wart formulation may include anti-wart drug carrier solvent and the coagulating agent. 所述溶剂载体可以包括含有至少一种挥发性溶剂的挥发性溶剂系统,和含有至少一种不挥发溶剂的不挥发溶剂系统。 The solvent carrier may comprise a volatile solvent system comprising at least one volatile solvent, and containing at least one non-volatile solvent is non-volatile solvent system. 所述制剂可以具有适合应用并且在挥发性溶剂系统蒸发前粘附于皮肤表面的粘度。 The formulation may be suitable for use with a volatile solvent system and prior to evaporation of the viscosity adhered to the skin surface. 当应用于皮肤表面时,该制剂在挥发性溶剂系统至少部分蒸发后形成固化层。 When applied to the skin surface, the formulation is formed at least partially cured layer after evaporation of the volatile solvent system. 甚至在挥发性溶剂系统至少基本蒸发后,抗疣激素持续以治疗上充足的速率被输送。 Even after the volatile solvent system is at least substantially evaporated, the anti-wart hormone is transported continuously at a sufficient rate of treatment.

[0126] 在另外的实施方式中,用于输送丙酸氯倍他索的制剂可以包括丙酸氯倍他索、溶剂载体和凝固剂。 Formulation [0126] In a further embodiment, the means for transporting clobetasol propionate may include clobetasol propionate, coagulating agent and a solvent carrier. 所述溶剂载体可以包括含有至少一种挥发性溶剂的挥发性溶剂系统,和不挥发溶剂系统。 The solvent carrier may comprise a volatile solvent system comprising at least one volatile solvent, and a non-volatile solvent system. 所述不挥发溶剂系统可以包括丙二醇和/或脂肪酸。 The non-volatile solvent system can include propylene glycol and / or fatty acid. 所述制剂可以具有适合应用并且在挥发性溶剂系统蒸发前粘附于皮肤表面的粘度。 The formulation may be suitable for use with a volatile solvent system and prior to evaporation of the viscosity adhered to the skin surface. 当应用于皮肤表面时,该制剂在挥发性溶剂系统至少部分蒸发后形成固化层。 When applied to the skin surface, the formulation is formed at least partially cured layer after evaporation of the volatile solvent system. 甚至在挥发性溶剂系统至少基本蒸发后,丙酸氯倍他索持续以治疗上充足的速率被输送。 Even after the volatile solvent system is at least substantially evaporated, clobetasol propionate continuous treatment at a sufficient rate to be conveyed. 所述凝固剂可以是基于蛋白质的凝固剂。 The coagulant may be based coagulant protein.

[0127] 在另一实施方式中,输送罗哌卡因的固化制剂可以包括罗哌卡因、溶剂载体和凝固剂。 [0127] In another embodiment, the delivery curable formulation may comprise ropivacaine ropivacaine, coagulating agent and a solvent carrier. 挥发性溶剂系统包括至少一种挥发性溶剂,而不挥发溶剂系统可包括溶剂诸如异硬脂酸、Span 20和甘油三乙酸酯。 The volatile solvent system comprises at least one volatile solvent, a volatile solvent system may not include a solvent, such as isostearic acid, Span 20 and glycerol triacetate. 所述制剂可以具有适合应用并且在挥发性溶剂系统蒸发前粘附于皮肤表面的粘度。 The formulation may be suitable for use with a volatile solvent system and prior to evaporation of the viscosity adhered to the skin surface. 当应用于皮肤表面时,该制剂在挥发性溶剂系统至少部分蒸发后形成固化层。 When applied to the skin surface, the formulation is formed at least partially cured layer after evaporation of the volatile solvent system. 甚至在至少一部分的挥发物部分蒸发后,罗哌卡因在挥发性溶剂系统至少基本上蒸发之后至少6小时内持续以不低于5mcg/h/cm2的速率被输送进入或穿过皮肤。 Even after at least a portion of the volatile portions were evaporated, ropivacaine after evaporation of the volatile solvent system is at least substantially continuously at least at a rate of not less than 6 hours 5mcg / h / cm2 is fed into or through the skin.

[0128] 在另一实施方式中,输送咪喹莫特的固化制剂可以包括咪喹莫特、溶剂载体和凝固齐U。 [0128] In another embodiment, the delivery of imiquimod curable formulation may include imiquimod, and solidifying solvent carrier together U. 挥发性溶剂系统包括至少一种挥发性溶剂,而不挥发溶剂系统可以包括如异硬脂酸、Span 20和甘油三乙酸酯的溶剂。 The volatile solvent system comprises at least one volatile solvent, without the volatile solvent system can include, for example isostearic acid, solvent, Span 20 and glycerol triacetate. 所述制剂可以具有适合应用并且在挥发性溶剂系统蒸发前粘附于皮肤表面的粘度。 The formulation may be suitable for use with a volatile solvent system and prior to evaporation of the viscosity adhered to the skin surface. 当应用于皮肤表面时,该制剂在挥发性溶剂系统至少部分蒸发后形成固化层。 When applied to the skin surface, the formulation is formed at least partially cured layer after evaporation of the volatile solvent system. 甚至在至少一部分的挥发物部分蒸发后,咪喹莫特在挥发性溶剂系统至少基本上蒸发后至少6小时内持续以不低于5mcg/h/cm2的速率被输送进入或穿过皮肤。 Even after at least a portion of the volatile portions were evaporated, imiquimod are delivered into or through the skin at a rate at least substantially volatile solvent evaporated system for at least not less than 5mcg / h / cm2 to 6 hours.

[0129] 在另一实施方式中,输送咪喹莫特的固化制剂可以包括咪喹莫特、溶剂载体和凝固齐U。 [0129] In another embodiment, the delivery of imiquimod curable formulation may include imiquimod, and solidifying solvent carrier together U. 挥发性溶剂系统包括至少一种挥发性溶剂,而不挥发溶剂系统可以包括如异硬脂酸、Span 20和甘油三乙酸酯的溶剂。 The volatile solvent system comprises at least one volatile solvent, without the volatile solvent system can include, for example isostearic acid, solvent, Span 20 and glycerol triacetate. 所述制剂可以具有适合应用并且在挥发性溶剂系统蒸发前粘附于皮肤表面的粘度。 The formulation may be suitable for use with a volatile solvent system and prior to evaporation of the viscosity adhered to the skin surface. 当应用于皮肤表面时,该制剂在挥发性溶剂系统至少部分蒸发后形成固化层。 When applied to the skin surface, the formulation is formed at least partially cured layer after evaporation of the volatile solvent system. 甚至在至少一部分的挥发物部分蒸发后,咪喹莫特在挥发性溶剂系统至少基本蒸发后至少6小时内持续以不低于O. 8mcg/h/cm2的速率被输送进入或穿过皮肤。 Even after at least a portion of the volatile portions were evaporated, imiquimod duration not less than a rate of at least O. 8mcg / h / cm2 is fed into or through the skin within 6 hours after the volatile solvent system is at least substantially evaporated.

[0130] 在另一实施方式中,输送酮洛芬的固化制剂可以包括酮洛芬、溶剂载体和凝固剂。 Curable formulation [0130] In another embodiment, the delivery may include ketoprofen ketoprofen, coagulating agent and a solvent carrier. 挥发性溶剂系统包括含有至少一种挥发性溶剂的挥发性溶剂系统以及包含甘油和丙二醇的不挥发溶剂系统。 Volatile solvent system comprising a volatile solvent system containing at least one volatile solvent comprises glycerol and propylene glycol and a non-volatile solvent system. 所述制剂可以具有适合应用并且在挥发性溶剂系统蒸发前粘附于皮肤表面的粘度。 The formulation may be suitable for use with a volatile solvent system and prior to evaporation of the viscosity adhered to the skin surface. 当应用于皮肤表面时,该制剂在挥发性溶剂系统至少部分蒸发后形成固化层。 When applied to the skin surface, the formulation is formed at least partially cured layer after evaporation of the volatile solvent system. 甚至在至少一部分的挥发物部分蒸发后,酮洛芬在挥发性溶剂系统至少基本上蒸发后至少6小时内持续以不低于10mcg/h/cm2的速率被输送进入或穿过皮肤。 Even after at least a portion of the volatile portions were evaporated, ketoprofen after evaporation of the volatile solvent system is at least substantially continuously at least at a rate of not less than 6 hours 10mcg / h / cm2 is fed into or through the skin.

[0131] 使用本发明的制剂和方法可以输送的其它药物包括润湿剂、软化剂和其它护肤化合物。 [0131] Other pharmaceutical formulations and methods of use of the present invention may be delivered include moisturizers, emollients and other skin care compounds.

实施例 Example

[0132] 以下实施例举例说明了当前最熟知的本发明的实施方式。 [0132] The following examples illustrate embodiments of the present invention, the most well known. 然而,应该理解,下文仅仅是本发明原理的典型的或示例性的应用。 However, it should be understood that the following are only exemplary or illustrative of the application of the principles of the present invention. 多种改变和可选组合物、方法、以及系统可由本领域普通技术人员在不背离本发明的精神和范围的情况下设计。 Various modifications and alternative compositions, methods, and systems may be designed in the case of ordinary skill in the art without departing from the spirit and scope of the invention. 所附的权利要求书意欲覆盖这类修改和安排。 The appended claims are intended to cover such modifications and arrangements. 因此,尽管上文已经具体地描述了本发明,但以下的实施例提供了关于当前认为是本发明最实际和优选的实施方式的进一步的细节。 Thus, although the foregoing has particularly described the present invention, the following examples provide information on what is currently considered the most practical and further details of the preferred embodiment of the present invention.

[0133] 实施例I [0133] Example I

[0134] 如前所述,无毛小鼠皮肤(HMS)或人表皮膜(HEM)被用作这里描述的体外通量研究的著名模型膜。 [0134] As described above, hairless skin (HMS) mouse or human epidermal membrane (HEM) are described herein as well-known model in vitro flux study. 无毛小鼠皮肤(HMS)被用作模型膜,进行这里描述的体外通量研究。 Hairless mouse skin (HMS) is used as a model membrane for in vitro flux study described herein. 从无毛小鼠腹部取得的新鲜分离的表皮被小心安放在Franz扩散池(diffusion cell)的供应小室和接受小室之间。 Freshly isolated hairless mouse abdominal skin never obtained was carefully placed between the Franz diffusion cell (diffusion cell) of the supply chamber and accepts chamber. 该接受小室装满PH 7. 4的磷酸盐缓冲盐水(PBS)。 The PH receiving chamber filled with phosphate buffered saline (PBS) 7. 4 in. 实验通过将(实施例2-5中的)测试制剂置于皮肤样品的角质层(SC)上而起始。 Initiated by adding experimental test formulations (in Example 2-5) was placed on the stratum corneum of the skin sample (SC). Franz池被置于维持在37°C的加热台上,并且HMS的温度被保持在35°C。 Franz cell is placed on the heating stage is maintained at 37 ° C, and the temperature is maintained at HMS 35 ° C. 在预设的时间间隔下,吸出800 μ L的试样并用新鲜的PBS溶液代替。 At a preset time interval, aspirated sample 800 μ L and replaced with fresh PBS solution. 皮肤通量(yg/Cm2/h)由渗透累积量对时间的曲线的稳态斜率加以确定。 Skin Flux (yg / Cm2 / h) is determined to be the time of the steady-state slope of the curve of the cumulative amount of permeation. 应该注意,人类尸体皮肤也可以用作体外通量研究的模型膜。 It should be noted that human cadaver skin model can also be used as a flux in vitro studies. 所用的皮肤安放和取样技术与上述HMS研究相同。 Skin and sampling techniques used in place of the above-described HMS same study.

[0135] 实施例2 [0135] Example 2

[0136] 人类尸体皮肤被用作选择二丙酸倍他米松的“促通量”不挥发溶剂的膜。 [0136] Human cadaver skin is used as a selection of betamethasone dipropionate "pro-flux" non-volatile solvent film. 约200mcL在各种溶剂中的BDP饱和溶液被加入到Franz池的供应腔室中。 About 200mcL BDP saturated solution in various solvents are added to the supply chamber of the Franz cell chamber. 实施例I中所述的体外分析被用于确定BDP的稳态通量。 Example I In vitro analysis of the embodiment is used to determine the steady-state flux of the BDP. 所用的体外方法在实施例I中描述。 An in vitro method used is described in Example I below. 皮肤中的活性酶将二丙酸倍他米松转化为倍他米松。 Enzyme activity in the skin betamethasone dipropionate converted to betamethasone. 表I中报告的稳态通量值是使用倍他米松外标(externalbetamethasone standard)进行量化的,并且被报告为每单位面积和时间的倍他米松渗透量。 Reported in Table I is the steady state flux values ​​using an external standard of betamethasone (externalbetamethasone standard) quantizing, and is reported as fold per unit area and time betamethasone permeation amount.

[0137] 表I—用于二丙酸倍他米松的不挥发溶剂 [0137] Table I- times for dipropionate Betamethasone nonvolatile solvent

[0138] [0138]

Figure CN102670567AD00261

[0139] *皮肤通量测量结果代表三次测定的平均值和标准偏差。 [0139] * Skin flux measurements represent the mean of triplicate determinations and standard deviation. 报告的通量测量结果是从累积量对时间曲线的线性区域确定的。 Flux measurements reported from the linear region of the cumulative amount versus time curve determined. 观察到该线性区域处于6-28小时之间。 The linear region was observed between 6-28 hours. 如果该实验继续,预期稳定状态也将继续。 If the experiment continues, it anticipated the steady state would continue.

[0140] 由结果可见,甘油三乙酸酯、labrasol、油酸和轻质矿物油具有与估计的IOng/cm2/hr治疗有效通量接近的通量值。 [0140] From the results can be seen, triacetin, Labrasol, oleic acid, and light mineral oil has an estimated IOng / cm2 / hr therapeutically effective flux through the closest value. 凝固剂和其它成分的加入可能会降低通量,因此上述不挥发溶剂可能不是“促通量”溶剂的理想选择。 Addition of coagulant and other ingredients may decrease the flux, so the above non-volatile solvents may not be ideal for "promoting flux" solvent. 然而,失水山梨糖醇单月桂酸酯具有比一个可能的治疗水平高三倍的通量,因此具有更好的机会成为“促通量”溶剂。 However, sorbitan monooleate than therapeutic levels of a possible three-fold higher flux, thus having a better chance to be "pro-flux" solvent. 其与多种凝固剂的相容性将确定其可以被使用的适当水平。 Compatibility with a variety of coagulant will determine the appropriate level may be used. 此外,丙二醇具有比所需治疗水平高19倍的通量,因此提供了明显高于测试的其它不挥发溶剂系统的通量。 Further, propylene glycol has a ratio of the desired therapeutic flux level 19 times higher, thus providing additional non-volatile solvent system throughput significantly higher than the test. 由于其它必要的或期望的成分掺入所述制剂往往降低通量,不挥发溶剂产生比仅仅很少“促通量”高得多的通量的能力可以是有利的,并且这可以允许在制剂中以相对低的药物浓度达到期望的治疗效果,这往往使制剂较便宜且更安全。 Since other necessary or desired ingredients into the formulation tends to decrease the flux, no less than just produce volatile solvent "to promote flux" a much higher throughput capability may be advantageous, and this can allow the formulation at a relatively low concentration of the drug in the desired therapeutic effect, which is often less expensive and safer the formulation.

[0141] 实施例3 [0141] Example 3

[0142] 在各种不挥发溶剂系统中的丙酸氯倍他索制剂被评估。 [0142] In various beclomethasone non-volatile solvent system clobetasol formulation was assessed. 所有的溶剂具有O. 1%(w/w)丙酸氯倍他索。 All solvents having clobetasol propionate O. 1% (w / w). 氯倍他索从测试制剂穿过HEM的渗透列于下面的表2。 Clobetasol penetration through the HEM from the test formulation set forth in Table 2 below.

[0143] 表2—用于丙酸氯倍他索的不挥发溶剂 [0143] Table 2 - Non-volatile solvents for the clobetasol propionate

[0144] [0144]

Figure CN102670567AD00271

[0145] [0145]

[0146] *皮肤通量测量结果代表三次测定的平均值和标准偏差。 [0146] * Skin flux measurements represent the mean of triplicate determinations and standard deviation. 报告的通量测量结果是从累积量对时间曲线的线性区域确定的。 Flux measurements reported from the linear region of the cumulative amount versus time curve determined. 观察到该线性区域处于6-28小时之间。 The linear region was observed between 6-28 hours. 如果该实验继续,预期稳定状态也将继续。 If the experiment continues, it anticipated the steady state would continue.

[0147] 人类尸体皮肤被用作选择丙酸氯倍他索的“促通量”溶剂的膜。 [0147] Human cadaver skin was used to select "pro flux" film solvent of clobetasol propionate. 体外方法在实施例I中描述。 Vitro method described in Example I below. 大约200mcl在各种不挥发溶剂中的O. 1% (w/w)氯倍他索溶液被加入到Franz池的供应腔室中。 In various 200mcl about nonvolatile solvents O. 1% (w / w) of clobetasol solution was added to the supply chamber of the Franz cell chamber. LC分析后获得的结果显示于表2。 LC analysis results obtained are shown in Table 2. 这里研究的所有纯不挥发溶液在30小时的时间段内具有在50ng/cm2/h以下的平均通量。 Studied here all the pure solution having a nonvolatile average flux at 50ng / cm2 / h or less in a period of 30 hours. 丙二醇和甘油具有对丙酸氯倍他索最低的渗透性。 Propylene glycol and glycerol having a permeability clobetasol propionate lowest. 考虑到结构上与丙酸氯倍他索相似的二丙酸倍他米松在丙二醇的情况下具有良好的通量,这个结果是令人吃惊的。 Considering the structure and clobetasol propionate similar betamethasone dipropionate having good flux in the case of propylene glycol, this result is surprising. 重量比9 : I的丙二醇和异硬脂酸混合物的溶剂系统具有比单独的任一溶剂或测试的其它溶剂显著更高的通量。 Weight ratio of 9: I in solvent system of propylene glycol and a mixture of isostearic acid have a significantly higher flux than any of the other solvents alone or a solvent tests. 平均通量比轻质矿物油——其似乎是最佳的非混合溶剂——高20倍。 The average flux ratio light mineral oil - which seems to be the best mixed solvents of a non - 20 times higher. 因此,对于丙酸氯倍他索,丙二醇/异硬脂酸提供了对于不挥发溶剂系统的最高通量。 Thus, for clobetasol propionate, propylene glycol / isostearic acid provides the highest throughput for non-volatile solvent system. 表2所列的不挥发溶剂中,仅9 : I的丙二醇:异硬脂酸被认为是促通量的。 Not listed in Table 2 in a volatile solvent, only 9: I propylene glycol: isostearic acid is considered to promote flux. 在本实施例中,促通量不挥发溶剂系统不是纯的单一物质,而是两种或多种物质在促通量比例下的混合物。 In the present embodiment, the non-volatile solvent system to promote the flux is not a pure single species, but two or more substances promoting the mixture at the flux ratio. 这正说明,其它比例或物质组合可以被用于产生促通量不挥发溶剂系统。 This is indicative of, or combination of substances other proportions may be used to produce non-volatile solvent system to promote flux.

[0148] 实施例4-9 [0148] Example 4-9

[0149] 制备含有O. 05% (w/w)丙酸氯倍他索的粘性制剂,其中含有丙二醇和异硬脂酸作为不挥发溶液和多种凝固剂。 Preparation of [0149] containing O. 05% (w / w) of clobetasol propionate viscous formulation containing propylene glycol and isostearic acid as a coagulant and a variety of non-volatile solution. 该制剂用表3中所列的成分制备。 The formulations are prepared with the ingredients listed in Table 3.

[0150] 表3——固化制剂组分 [0150] Table 3-- curable formulation components

[0151] [0151]

Figure CN102670567AD00281

[0152] [0152]

[0153] 研究上述每种组合物对丙酸氯倍他索的通量,如下面表4所示: [0153] Each of the above studies on the flux composition clobetasol propionate, as shown in the following Table 4:

[0154] 表4—丙酸氯倍他索在35°C穿过人类尸体皮肤的稳态通量 [0154] Table 4 - clobetasol propionate at 35 ° C steady state flux through human cadaver skin

[0155] [0155]

Figure CN102670567AD00282

[0156] *皮肤通量测量结果代表三次测定的平均值和标准偏差。 [0156] * Skin flux measurements represent the mean of triplicate determinations and standard deviation. 报告的通量测量结果是从累积量对时间曲线的线性区域确定的。 Flux measurements reported from the linear region of the cumulative amount versus time curve determined. 观察到该线性区域处于6-28小时之间。 The linear region was observed between 6-28 hours. 如果该实验继续,预期稳定状态也将继续。 If the experiment continues, it anticipated the steady state would continue.

[0157] 由表4可见,实施例4中所述的、含有聚乙烯醇作为凝固剂的制剂具有高的丙酸氯倍他索通量。 [0157] From Table 4, described in Example 4, containing polyvinyl alcohol having a high flux of clobetasol propionate formulation as a coagulant. 已知聚乙烯醇形成可拉伸的固化层并且该制剂具有可接受的耐磨性是可能的。 Known polyvinyl alcohol to form a cured layer of a stretchable and the formulation having acceptable abrasion resistance is possible. 如果需要,产生的固化层的韧性可以通过加入适当的增塑剂进行改变(不挥发溶剂系统本身也起增塑剂的作用)。 If desired, the toughness of the cured layer produced can be varied (non-volatile solvent system itself also functions as a plasticizer) by adding an appropriate plasticizer. 粘性也可以通过加入适当量的增粘剂或通过加入适当量的另一种凝固剂,如dermacryl 97,进行改变。 Another coagulant may be viscous by adding an appropriate amount of a thickener or by adding an appropriate amount of such dermacryl 97, changes.

[0158] 关于实施例9中所述的制剂,需要更高比例的乙醇来溶解该聚合物。 [0158] For the formulation according to Example 9, a higher proportion of ethanol to dissolve the polymer. 然而,在研究的凝固剂中,实施例9中使用的凝固剂提供了最高的丙酸氯倍他索通量。 However, in the study of the coagulant, the coagulant used in Example 9 embodiment provides the highest throughput clobetasol propionate. 该制剂的耐磨性可以通过加入适当水平的其它成分改变,所述其它成分包括但不限于增塑剂、增粘剂、不挥发溶剂和/或凝固剂。 Abrasion resistance of the formulation may be varied by the addition of suitable levels of other ingredients, the additional ingredients including, but not limited to, plasticizers, tackifiers, non-volatile solvent and / or coagulant. [0159] 实施例10 [0159] Example 10

[0160] 评估了在多种不挥发溶剂系统中的阿昔洛韦制剂。 [0160] Evaluation of the acyclovir formulation in a variety of non-volatile solvent system. 过量的阿昔洛韦存在。 There is an excess of acyclovir. 阿昔洛韦从测试制剂穿透HMS的渗透性列于下面的表5。 Acyclovir penetration from test formulation HMS permeability listed below in Table 5.

[0161]表 5 [0161] TABLE 5

[0162] [0162]

[0163] [0163]

Figure CN102670567AD00291

[0164] *皮肤通量测量结果代表三次测定的平均值和标准偏差。 [0164] * Skin flux measurements represent the mean of triplicate determinations and standard deviation. 报告的通量测量结果是从累积量对时间曲线的线性区域确定的。 Flux measurements reported from the linear region of the cumulative amount versus time curve determined. 观察到该线性区域处于4-8小时之间。 The linear region was observed between 4-8 hours. 如果实验条件允许,稳态输送可能持续远超过8小时。 If the experiment conditions permit, the steady-state transport is likely to continue far more than eight hours.

[0165] 通过将200mcL阿昔洛韦置于无毛小鼠皮肤的角质层一侧(供应)获得阿昔洛韦在上述不挥发溶剂中的稳态通量。 [0165] In the flux to obtain a steady state acyclovir nonvolatile solvent by 200mcL placed on the stratum corneum side of acyclovir hairless mouse skin (supplied). 该体外研究按照实施例I所述进行。 This in vitro study was performed according to Example I. 令人吃惊的结果显示了聚乙二醇400、span 80、油酸乙酯、或油酸乙酯加三乙醇胺对阿昔洛韦是不促通量的溶剂(例如,稳态通量值明显低于表I中所注的上市产品中的阿昔洛韦的稳态通量,其中所述通量约为3mcg/cm2/h)。 The results show the surprising polyethylene glycol 400, span 80, ethyl oleate, ethyl oleate, or triethanolamine plus acyclovir is not a chaotropic agent flux (e.g., steady state flux values ​​significantly Note in table I below listed products acyclovir steady state flux, wherein the flux is about 3mcg / cm2 / h). 然而,异硬脂酸和三乙醇胺组合或者油酸和增加量的三乙醇胺的组合对阿昔洛韦是促通量溶剂。 However, a combination of isostearic acid and triethanolamine, or a combination of triethanolamine and oleic acid increased amount of flux Acyclovir is a pro-solvent. 可见,使用30%三乙醇胺与油酸作为不挥发溶剂系统获得最高的通量。 Visible, using 30% triethanolamine oleate as a non-volatile solvent system to obtain the highest throughput.

[0166]实施例 11-14 [0166] Examples 11-14

[0167] 如下制备原型制剂(prototype formulation)。 [0167] Formulation prototype (prototype formulation) was prepared as follows. 根据表6,按照本发明的实施例制备若干阿昔洛韦固化制剂,如下: According to Table 6, several acyclovir formulations cured according to an embodiment of the present invention is prepared as follows:

[0168]表 6 [0168] TABLE 6

Figure CN102670567AD00301

[0170] 在实施例11-14中,如下制备表6中的组合物。 [0170] In the compositions of Examples 11-14 in Table 6 was prepared as follows. Eudragit RL-P0和乙醇在玻璃罐中混合并在搅拌下加热直到RL-PO溶解。 Eudragit RL-P0 and ethanol were mixed in a glass jar and heated with stirring until dissolved RL-PO. 异硬脂酸和三乙醇胺被加入到RL-PO/乙醇的混合物中并且该混合物被剧烈搅拌。 Isostearic acid and triethanolamine were added to the mixture RL-PO / ethanol and the mixture was vigorously stirred. 一旦获得均一的混合物,阿昔洛韦被加入到该混合物中并且该制剂被剧烈混合。 Once a homogeneous mixture is obtained, acyclovir is added to the mixture and the formulation was vigorously mixed.

[0171]实施例 15-16 [0171] Examples 15-16

[0172] 如下制备原型制剂。 [0172] Prototype formulations prepared as follows. 根据表7,按照本发明的实施方式制备若干阿昔洛韦固化制齐U,如下: According to Table 7, several embodiments of acyclovir prepared according to the curing system of the present invention together U, as follows:

[0173]表 7 [0173] TABLE 7

Figure CN102670567AD00302

[0175] 表3中显示的实施例15和16的组合物如下进行制备。 [0175] The compositions of Examples 15 and 16 shown in Table 3 were prepared as follows. Eudragit RL-PO和乙醇在玻璃罐中混合并在搅拌下加热直到RL-PO溶解。 Eudragit RL-PO and ethanol were mixed in a glass jar and heated with stirring until dissolved RL-PO. 异硬脂酸和二异丙醇胺或NeutiOl TE多元醇(BASF)被加入到RL-PO/乙醇混合物中,并且该混合物被剧烈搅拌。 Isostearic acid and diisopropanolamine or NeutiOl TE polyol (BASF) is added to the RL-PO / ethanol mixture, and the mixture was vigorously stirred. 一旦获得均一混合物,阿昔洛韦被加入到该混合物中,并且该制剂被剧烈混合。 Once a homogeneous mixture is obtained, acyclovir is added to the mixture and the formulation was vigorously mixed.

[0176]实施例 17-18 [0176] Example 17-18

[0177] 如下制备原型剥离制剂。 [0177] Prototype release formulations prepared as follows. 根据表8,按照本发明的实施方式制备若干阿昔洛韦固化制剂,如下: According to Table 8, cured several acyclovir formulations are prepared according to an embodiment of the present invention, as follows:

[0178]表 8 [0178] TABLE 8

Figure CN102670567AD00311

[0180] 在实施例17-18中,表8中的组合物如下进行制备。 [0180] In Example 17-18, Table 8 composition was prepared as follows. 来自Aqualon的乙基纤维素(EC) Ν7或EC NlOO和乙醇在玻璃罐中混合并在搅拌下加热直到固态纤维素溶解。 Ethyl cellulose (EC) Ν7 or EC NlOO and ethanol were mixed in a glass jar from Aqualon and heated with stirring until the solid cellulose is dissolved. 异硬脂酸和三乙醇胺被加入到纤维素/乙醇混合物中并且该混合物被剧烈搅拌。 Isostearic acid and triethanolamine were added to the cellulose / ethanol mixture and the mixture was vigorously stirred. 一旦获得均一的混合物,阿昔洛韦被加入到混合物中并且该制剂被剧烈混合。 Once a homogeneous mixture is obtained, acyclovir is added to the mixture and the formulation was vigorously mixed.

[0181] 实施例19 [0181] Example 19

[0182] 实施例11-18的制剂在实施例I所述的无毛小鼠皮肤(HMS)体外模型中测试。 [0182] Formulation Example 11-18 Test of the embodiment according to Example I in the hairless mouse skin (HMS) in vitro models. 表9显示了用上文概述的试验方法获得的数据。 Table 9 shows the data obtained with the test methods outlined above.

[0183] 表9——阿昔洛韦穿过HMS的稳态通量(J) [0183] Table 9-- steady state flux of acyclovir through the HMS (J)

[0184] [0184]

Figure CN102670567AD00312

[0185] *皮肤通量测量结果代表三次测定的平均值和标准偏差。 [0185] * Skin flux measurements represent the mean of triplicate determinations and standard deviation. 报告的通量测量结果是从累积量对时间曲线的线性区域确定的。 Flux measurements reported from the linear region of the cumulative amount versus time curve determined. 观察到该线性区域处于4-8小时之间。 The linear region was observed between 4-8 hours. 如果实验条件允许,稳态输送将延伸超过所测量的8小时。 If the experiment conditions permit, the conveyor extends beyond the steady state measured for 8 hours.

[0186] 上面显示的本发明的制剂一般地提供了活性成分的显著渗透性,并且进一步地,实施例11-13和18的制剂被发现比市场化产品Zovirax乳膏(Zovirax Cream)具有高得多的渗透性。 [0186] The preparation of the present invention shown above provides a significant permeability of the active ingredient in general, and further, Formulation Examples 11-13 and 18 were found than the market product Zovirax cream (Zovirax Cream) having a high more permeability. 对于实施例11、12和Zovirax Cream,随时间渗透穿过HMS角质层的阿昔洛韦的量被示于图4。 For Examples 11, 12 and Zovirax Cream, over time, the amount of acyclovir permeation through the stratum corneum HMS 4 is shown in FIG. 所显示的每个值表示至少三次试验的平均值土SD(标准偏差)。 Each value shown represents the average of at least three tests of soil SD (standard deviation).

[0187] 实施例11-14显示了三乙醇胺与异硬脂酸(ISA)的比例对阿昔洛韦通量增强的影响。 [0187] Examples 11-14 show the effect of triethanolamine and isostearic acid (ISA) of the ratio of the flux enhancing acyclovir. 最优的ISA :三乙醇胺的比例为I : I到2 : I并且大于4 : I的比例表现出阿昔洛韦皮肤通量的显著降低。 Optimal ISA: triethanolamine ratio of I: I to 2: I and greater than 4: I ratio showed a significant decrease in skin flux of acyclovir. 加入二异丙醇胺和Neutrol代替制剂中的三乙醇胺(实施例15和16)表现出阿昔洛韦通量的明显降低。 Neutrol and diisopropanolamine was added instead of triethanolamine in the formulation (Examples 15 and 16) showed a significantly lower flux acyclovir. 这可能是由于三乙醇胺和ISA之间的特定化学相互作用在制剂中创建了促进更高皮肤通量的环境。 This may be due to a specific chemical interaction between interaction triethanolamine and ISA promote higher skin flux creates an environment in the formulation. 实施例17和18使用了不同的凝固剂,以评估凝固剂对阿昔洛韦通量的影响。 Examples 17 and 18 using a different coagulant, coagulant to assess the effect of acyclovir flux. 令人惊讶地,实施例17显示了阿昔洛韦皮肤通量的显著降低,但是实施例18——其与实施例17的不同仅仅在于凝固剂的分子量——与实施例11中相似的ISA :三乙醇胺比例相比,显示出对阿昔洛韦皮肤通量没有影响。 Surprisingly, Example 17 showed a significant reduction acyclovir skin flux, but Example 18-- Example 17 which differs from the embodiment only in that the molecular weight coagulant - similar to Example 11 ISA : triethanolamine proportion compared, showing no effect on acyclovir skin flux.

[0188] 由图4可以看出,实施例11和12显示出阿昔洛韦长达8小时的持续输送,合理的是,基于药物荷载和不挥发溶剂的持续存在,假设阿昔洛韦将以报告的通量值持续输送与受试者期望将该固化制剂保留粘附于皮肤上一样长的时间。 [0188] As can be seen from Figure 4, Examples 11 and 12 showed sustained acyclovir transport up to 8 hours, it is reasonable, based on the drug load and nonvolatile solvent persists, will assume acyclovir flux values ​​reported in the subject sustained delivery formulation is desirable to retain adhered to the cured as long time on the skin.

[0189] 实施例20 [0189] Example 20

[0190] 类似于实施例12的固化制剂(无阿昔洛韦)被应用到人的皮肤表面,产生薄的、透明的、柔软且可拉伸的固化层。 Transparent, flexible and stretchable cured layer is cured formulation (without acyclovir) Example 12 [0190] embodiment is similar to that applied to the skin surface of a human, resulting thin. 挥发性溶剂(乙醇)蒸发数分钟后,形成可剥离的固化粘合层。 After the volatile solvent (ethanol) was evaporated minutes, forming a cured adhesive layer may be peeled off. 可拉伸固化层具有对皮肤的良好粘着性并且不会与皮肤分离,而且可以容易地从皮肤上剥离。 Stretchable cured layer having good adhesion to the skin and does not separate from the skin, but can be easily peeled from the skin. 缺乏阿昔洛韦对该制剂和软的粘结固体的物理性质和耐磨性有最小的影响,因为当其存在时,是以如此之低的浓度存在的。 Lack of acyclovir have a minimal effect on the physical properties and abrasion resistance of the adhesive formulation and soft solids, because when it is present, is so low concentrations present.

[0191] 实施例21 [0191] Example 21

[0192] 评估了在多种不挥发溶剂系统中的酮洛芬固化制剂。 [0192] Evaluation of the curable formulation of ketoprofen in a variety of non-volatile solvent system. 过量的酮洛芬存在。 An excess of ketoprofen. 酮洛芬从测试制剂穿透HMS的渗透性列于下面的表10。 Ketoprofen penetrates from HMS permeability test formulations are listed in Table 10 below.

[0193]表 10 [0193] TABLE 10

[0194] [0194]

Figure CN102670567AD00321

[0195] *皮肤通量测量结果代表三次测定的平均值和标准偏差。 [0195] * Skin flux measurements represent the mean of triplicate determinations and standard deviation. 报告的通量测量结果是从累积量对时间曲线的线性区域确定的。 Flux measurements reported from the linear region of the cumulative amount versus time curve determined. 观察到该线性区域处于4-8小时之间。 The linear region was observed between 4-8 hours. 如果实验条件允许,稳态输送可能持续远超过8小时。 If the experiment conditions permit, the steady-state transport is likely to continue far more than eight hours.

[0196] 通过将200mcL置于无毛小鼠皮肤的角质层侧(供应),获得通过上述不挥发溶剂的酮洛芬稳态通量。 [0196] placed on the stratum corneum side by 200mcL hairless mouse skin (supply), a steady state flux of ketoprofen is obtained by the above-described non-volatile solvents. 体外研究按照实施例I所述进行。 In vitro studies were performed as described in Example I. 从表10可见,不挥发溶剂甘油和聚乙二醇400具有低稳态通量值并且将不被认为是“促通量的”。 10 seen from the table, non-volatile glycerol and polyethylene glycol 400 solvent having a low steady-state flux values ​​and will not be considered to be "pro-flux." Span20可被认为是促通量的,而丙二醇或油酸提供了最高的通量并且被认为是促通量不挥发溶剂系统。 Span20 may be considered to promote flux, and propylene glycol or oleic acid provides the highest flux and the flux is considered to promote non-volatile solvent system. 促通量溶剂的评价是基于估计的治疗有效酮洛芬通量(表A中的16mcg/cm2/h)。 Evaluation of flux solvent to promote the treatment is based on the estimated effective flux of ketoprofen (Table A 16mcg / cm2 / h). 低于治疗有效通量(表A)的、通过不挥发溶剂的药物稳态通量值不被认为是促通量的,而高于所述治疗有效通量值的、通过不挥发溶剂的药物稳态通量值被认为是促通量的。 A therapeutically effective flux below (Table A), the steady state flux values ​​through drug nonvolatile solvent is not considered to be pro-flux, but higher than the therapeutically effective flux values, not by the drug solvent evaporation steady-state flux values ​​are considered to be pro-flux.

[0197] 实施例22 [0197] Example 22

[0198] 评估了在多种不挥发溶剂系统中的罗哌卡因固化制剂。 [0198] Evaluation of the curable agent ropivacaine in various non-volatile solvent system. 过量的罗哌卡因存在。 The presence of an excess of ropivacaine. 罗哌卡因从测试制剂穿透HMS的渗透性列于下面的表11。 HMS ropivacaine from penetrating permeability test formulations are listed in Table 11 below.

[0199]表 11 [0200] [0199] Table 11 [0200]

Figure CN102670567AD00331

[0201] *皮肤通量测量结果代表三次测定的平均值和标准偏差。 [0201] * Skin flux measurements represent the mean of triplicate determinations and standard deviation. 报告的通量测量结果是从累积量对时间曲线的线性区域确定的。 Flux measurements reported from the linear region of the cumulative amount versus time curve determined. 观察到该线性区域处于4-8小时之间。 The linear region was observed between 4-8 hours. 如果实验条件允许,稳态输送可能持续远超过8小时。 If the experiment conditions permit, the steady-state transport is likely to continue far more than eight hours.

[0202] 通过将200mcL置于无毛小鼠皮肤的角质层侧(供应),获得通过上述不挥发溶剂的罗哌卡因碱稳态通量。 [0202] placed on the stratum corneum side by 200mcL hairless mouse skin (supply), to obtain a steady state flux of ropivacaine base by the above-described non-volatile solvents. 体外研究按照实施例I所述进行。 In vitro studies were performed as described in Example I. 由表11可见,不挥发溶剂甘油和Tween 20具有低稳态通量值并且将不被认为是“促通量的”。 Seen from Table 11, non-volatile solvent Glycerol and Tween 20 have a low steady-state flux values ​​and will not be considered to be "pro-flux." 然而,矿物油和异硬脂酸是促通量溶剂并且是与凝固剂和挥发性溶剂一起进行评估以设计可接受的固化制剂的良好候选物。 However, mineral oil and isostearic acid and the solvent is a pro flux is evaluated together with the coagulating agent and a volatile solvent formulation designed acceptable cure good candidate. 令人吃惊地,Span20具有高得多的稳态通量值并且具有高促通量溶剂的资格。 Surprisingly, Span20 has a steady state flux values ​​and a much higher throughput to promote a high qualified solvent. 低于治疗有效通量(表A)的、通过不挥发溶剂的药物稳态通量值不被认为是促通量的,而高于治疗有效通量的、通过不挥发溶剂的药物稳态通量值被认为是促通量的。 A therapeutically effective flux below (Table A), the steady state flux values ​​through drug nonvolatile solvent is not considered to be pro-flux, but higher than the therapeutically effective flux through the non-volatile solvent through steady-state drug value is considered to be pro-flux.

[0203] 实施例23 [0203] Example 23

[0204] 评估了在多种不挥发溶剂系统中的双氯芬酸钠(从Spectrum获得)固化制剂。 [0204] Evaluation of diclofenac sodium in various non-volatile solvent system (obtained from Spectrum) curable formulation. 过量的双氯芬酸钠存在。 There is an excessive amount of diclofenac sodium. 双氯芬酸钠从测试制剂穿透HMS的渗透性列于下面的表12。 HMS penetration of diclofenac sodium from the formulation permeability test are shown in Table 12 below.

[0205]表 12 [0205] Table 12

[0206] [0206]

不挥发溶剂系统皮肤通量* (mcg/cm2/h) Non-volatile solvent system Skin Flux * (mcg / cm2 / h)

甘油 I. 7 + 0. 3 I. 7 + 0. 3 Glycerin

Figure CN102670567AD00341

[0207] [0207]

[0208] *皮肤通量测量结果代表三次测定的平均值和标准偏差。 [0208] * Skin flux measurements represent the mean of triplicate determinations and standard deviation. 报告的通量测量结果是从累积量对时间曲线的线性区域确定的。 Flux measurements reported from the linear region of the cumulative amount versus time curve determined. 观察到该线性区域处于4-8小时之间。 The linear region was observed between 4-8 hours. 如果实验条件允许,稳态输送可能持续远超过8小时。 If the experiment conditions permit, the steady-state transport is likely to continue far more than eight hours.

[0209] 通过将200mcL置于无毛小鼠皮肤的角质层侧(供应),获得通过上述不挥发溶剂的双氯芬酸钠稳态通量。 [0209] placed on the stratum corneum side by 200mcL hairless mouse skin (supply), a steady state flux of diclofenac sodium obtained by the above-described non-volatile solvents. 体外研究按照实施例I所述进行。 In vitro studies were performed as described in Example I. 由表12可见,不挥发溶剂甘油具有与估计的治疗稳态通量值相当的稳态通量值并且可被认为是促通量溶剂。 12 seen from the table, having a non-volatile solvent Glycerol therapeutic steady state flux values ​​corresponding to the estimated steady-state flux values ​​and may be considered to promote the flux solvent. 然而,肉豆蘧酸异丙酯、油酸乙酯、丙二醇和Span 20的稳态通量值是报告的甘油通量值的至少10倍。 However, myristoyl Qu isopropyl myristate, ethyl oleate, propylene glycol, and steady-state flux values ​​Span 20 is at least 10 times the values ​​reported on glycerol. 这些不挥发溶剂被认为是促通量溶剂。 These solvents are considered non-volatile solvent is a pro flux.

[0210] 实施例24 [0210] Example 24

[0211] 评估了在多种不挥发溶剂系统中的双氯芬酸固化制剂。 [0211] Assessment of the cured formulation of diclofenac in various non-volatile solvent system. 过量的双氯芬酸存在。 Presence of excess diclofenac. 双氯芬酸从测试制剂穿透HMS的渗透性列于下面的表13。 Diclofenac from penetrating HMS permeability test formulations are listed in Table 13 below.

[0212]表 13 [0212] TABLE 13

[0213] [0213]

Figure CN102670567AD00342

[0214] *皮肤通量测量结果代表三次测定的平均值和标准偏差。 [0214] * Skin flux measurements represent the mean of triplicate determinations and standard deviation. 报告的通量测量结果是从累积量对时间曲线的线性区域确定的。 Flux measurements reported from the linear region of the cumulative amount versus time curve determined. 观察到该线性区域处于4-8小时之间。 The linear region was observed between 4-8 hours. 如果实验条件允许,稳态输送可能持续远超过8小时。 If the experiment conditions permit, the steady-state transport is likely to continue far more than eight hours.

[0215] 通过将200mcL置于无毛小鼠皮肤的角质层侧(供应),获得来自上述不挥发溶剂的双氯芬酸稳态通量。 [0215] placed on the stratum corneum side by 200mcL hairless mouse skin (supply), a steady state flux of diclofenac obtained from the non-volatile solvent. 体外研究按照实施例I所述进行。 In vitro studies were performed as described in Example I. 由表13可见,不挥发溶剂甘油不具有报告的稳态通量值并且不被认为是可行的不挥发溶剂候选。 Seen from Table 13, no non-volatile solvent Glycerol has a steady state flux values ​​reported and are not considered a viable candidate for a nonvolatile solvent. 然而,肉豆蘧酸异丙酯、油酸乙酯、丙二醇和Span 20的稳态通量值不超过报告的当前市场上可获得产品通量值的10倍,并因此可以被认为是促通量溶剂。 However, the product obtained through 10 times the value Qu myristoyl isopropyl, ethyl oleate, propylene glycol, and steady-state flux values ​​Span 20 does not exceed the current market reporting, and thus can be considered facilitation The amount of solvent. 应该注意的是,从上述不挥发溶剂中的每一种的双氯酚酸稳态通量值比使用双氯酚酸钠获得的稳态通量值低得多。 It should be noted that the much lower steady state flux values ​​from said nonvolatile solvent each of diclofenac than the steady-state flux values ​​obtained diclofenac. 因此,如果需要提高治疗有效通量值,使用促通量不挥发溶剂和双氯酚酸的盐形式将可能产生比使用双氯酚酸的酸形式更高的稳态通量。 Thus, if desired to improve the therapeutically effective flux values, promote the use of volatile solvents and without the flux of diclofenac salt form will likely be higher than the acid used in the form of steady state flux of diclofenac.

[0216] 实施例25 [0216] Example 25

[0217] 评估了在多种不挥发溶剂系统中的睾酮固化制剂。 [0217] Evaluation of the curable formulation of testosterone in various non-volatile solvent system. 过量的睾酮存在。 There is an excess of testosterone. 睾酮从测试制剂穿透HMS的渗透性列于下面的表14。 HMS testosterone penetration from test formulation set forth in Table permeability below 14.

[0218]表 14 [0218] TABLE 14

[0219] [0219]

Figure CN102670567AD00351

[0220] *皮肤通量测量结果代表三次测定的平均值和标准偏差。 [0220] * Skin flux measurements represent the mean of triplicate determinations and standard deviation. 报告的通量测量结果是从累积量对时间曲线的线性区域确定的。 Flux measurements reported from the linear region of the cumulative amount versus time curve determined. 观察到该线性区域处于4-8小时之间。 The linear region was observed between 4-8 hours. 如果实验条件允许,稳态输送可能持续远超过8小时。 If the experiment conditions permit, the steady-state transport is likely to continue far more than eight hours.

[0221] 通过将200mcL置于无毛小鼠皮肤的角质层侧(供应),获得通过上述不挥发溶剂的睾酮稳态通量。 [0221] placed on the stratum corneum side by 200mcL hairless mouse skin (supply), to obtain a steady state flux of testosterone through said nonvolatile solvent. 体外研究按照实施例I所述进行。 In vitro studies were performed as described in Example I. 由表14可见,不挥发溶剂TweeneO (聚氧乙烯失水山梨糖醇单硬脂酸酯)不具有可报告的稳态通量值并且不被认为是可行的不挥发溶剂候选。 14 seen from the table, non-volatile solvent TweeneO (polyoxyethylene sorbitan monostearate) does not have a steady-state flux values ​​can be reported and are not considered a viable candidate for a nonvolatile solvent. 然而,Span 20、聚乙二醇400、异硬脂酸和丙二醇的稳态通量值具有与当前市场上可获得的产品相当的稳态通量值(表A),因此可以被认为是促通量溶剂。 However, Span 20, polyethylene glycol 400, a steady state flux values ​​and propylene glycol isostearate having available on the market and the products corresponding to the steady-state flux values ​​(Table A), can thus be considered to promote flux solvent. 但是,尽管除Tween 60之外的所有不挥发溶剂都是促通量的,但丙二醇对实际制剂而言可能更优,因为其产生的高通量意味着在较小的皮肤接触面积下可以输送相同量的药物。 However, despite all the non-volatile solvent other than Tween 60 are pro-flux, but the actual glycol formulations may be better, because it produces a high flux means may be transported at a small skin contact area the same amount of the drug.

[0222] 实施例26 [0222] Example 26

[0223] 评估了在多种不挥发溶剂系统中的盐酸氢吗啡酮(hydromorphone HCl)固化制齐U。 [0223] Hydromorphone HCl evaluated in a variety of non-volatile solvent system (hydromorphone HCl) manufactured by curing together U. 过量的盐酸氢吗啡酮存在。 Excess presence of hydromorphone hydrochloride. 盐酸氢吗啡酮从测试制剂穿透HMS的渗透性列于下面的表15。 Hydromorphone Hydrochloride from penetrating HMS permeability test formulation set forth in Table 15 below.

[0224]表 15 [0224] TABLE 15

[0225] [0225]

Figure CN102670567AD00352

[0226] *皮肤通量测量结果代表三次测定的平均值和标准偏差。 [0226] * Skin flux measurements represent the mean of triplicate determinations and standard deviation. 报告的通量测量结果是从累积量对时间曲线的线性区域确定的。 Flux measurements reported from the linear region of the cumulative amount versus time curve determined. 观察到该线性区域处于4-8小时之间。 The linear region was observed between 4-8 hours. 如果实验条件允许,稳态输送可能持续远超过8小时。 If the experiment conditions permit, the steady-state transport is likely to continue far more than eight hours.

[0227] 通过将200mcL置于无毛小鼠皮肤的角质层侧(供应),获得从上述不挥发溶剂的氢吗啡酮稳态通量。 [0227] placed on the stratum corneum side by 200mcL hairless mouse skin (supply), a steady state flux of hydromorphone obtained from the non-volatile solvent. 体外研究按照实施例I所述进行。 In vitro studies were performed as described in Example I. 由表15可见,不挥发溶剂丙二醇和异硬脂酸可适合作为促通量溶剂(基于估计的氢吗啡酮治疗有效通量为2mcg/cm2/h)。 Seen from Table 15, non-volatile solvent, propylene glycol and isostearic acid suitable as pro flux solvent (based on the estimated effective therapeutic hydromorphone flux 2mcg / cm2 / h). 明显地,来自油酸乙酯的氢吗啡酮稳态通量值高得多并且适合作为高促通量溶剂。 Obviously, much higher steady-state flux values ​​hydromorphone from ethyl oleate and is suitable as a high throughput promoting solvent.

[0228] 实施例27 [0228] Example 27

[0229] 评估了在多种不挥发溶剂系统中的氢吗啡酮(hydromorphone)固化制剂。 [0229] evaluated the hydromorphone in a variety of non-volatile solvent system (hydromorphone) curable formulation. 过量的氢吗啡酮存在。 The presence of an excess of hydromorphone. 氢吗啡酮从测试制剂穿透HMS的渗透性列于下面的表16。 Hydromorphone from the formulation to penetrate the HMS permeability test are shown in Table 16 below.

[0230] 表16 [0231] [0230] Table 16 [0231]

Figure CN102670567AD00361

[0232] *皮肤通量测量结果代表三次测定的平均值和标准偏差。 [0232] * Skin flux measurements represent the mean of triplicate determinations and standard deviation. 报告的通量测量结果是从累积量对时间曲线的线性区域确定的。 Flux measurements reported from the linear region of the cumulative amount versus time curve determined. 观察到该线性区域处于4-8小时之间。 The linear region was observed between 4-8 hours. 如果实验条件允许,稳态输送可能持续远超过8小时。 If the experiment conditions permit, the steady-state transport is likely to continue far more than eight hours.

[0233] 通过将200 μ L置于无毛小鼠皮肤的角质层侧(供应),获得从上述不挥发溶剂的氢吗啡酮稳态通量。 [0233] positioned by 200 μ L corneum side of hairless mouse skin (supply), obtained from the non-volatile solvent hydromorphone above steady-state flux. 体外研究按照实施例I所述进行。 In vitro studies were performed as described in Example I. 由表16可见,不挥发溶剂丙二醇可适合作为促通量溶剂(基于估计的氢吗啡酮治疗有效通量为2yg/cm2/h)。 Seen from the table 16, nonvolatile solvent is propylene glycol suitable as pro flux solvent (based on the estimated effective therapeutic hydromorphone flux 2yg / cm2 / h). 明显地,来自异硬脂酸和油酸乙酯的氢吗啡酮稳态通量值也适合作为促通量溶剂。 Obviously, hydromorphone from the steady-state flux values ​​of isostearic acid and ethyl oleate are also suitable as flux promoting solvent.

[0234]实施例 28-32 [0234] Example 28-32

[0235] 如下制备原型制剂。 [0235] Prototype formulations prepared as follows. 根据表17,按照本发明的实施例制备若干制剂,如下: According to Table 17, a number of formulations prepared according to embodiments of the present invention, as follows:

[0236]表 17 [0236] Table 17

[0237] [0237]

Figure CN102670567AD00362
Figure CN102670567AD00371

[0238] [0238]

[0239] 实施例28-32的固化制剂以如下方式制备: [0239] Examples 28-32 cured formulation prepared in the following manner:

[0240] 籲凝固剂溶解在挥发性溶剂中(例如,在水中溶解聚乙烯醇,在乙醇中溶解Eudragit 聚合物), [0240] Calls coagulant is dissolved in a volatile solvent (e.g., polyvinyl alcohol dissolved in water, the polymer was dissolved in ethanol Eudragit),

[0241] •不挥发溶剂与凝固剂/挥发性溶剂混合物混合。 [0241] • nonvolatile solvent / volatile solvent mixture mixed coagulating agent.

[0242] •产生的溶液被剧烈充分混合数分钟。 Solution [0242] • produce is thoroughly mixed violently for several minutes.

[0243] •药物随后被加入并且该制剂被再次混合数分钟。 [0243] • medicament is then added and the formulation was again mixed for several minutes.

[0244] 在上述所有实施例中,促通量不挥发溶剂/凝固剂/挥发性溶剂组合是相容的,这由显示出合适干燥时间并提供可拉伸的固化层和药物稳态通量的均一、单相系统证明(见下文实施例33)。 [0244] In all the above embodiments, the flux does not promote volatilization of the solvent / coagulating agent / volatile solvent combinations are compatible, and which provides a cured layer of a stretchable and a steady state flux of the drug by the display of a suitable drying time the homogeneous, single-phase system demonstrated (see Example 33 below).

[0245] 实施例33 [0245] Example 33

[0246] 实施例中的制剂在实施例I所述的无毛小鼠皮肤(HMS)或HEM体外模型中测试。 [0246] The embodiment or embodiments formulation tested in vitro model HEM Example I in the hairless skin (HMS) mice. 表18显示了使用上述实验方法获得的数据。 Table 18 shows the data obtained using the experimental methods.

[0247] 表18——稳态通量(J) [0247] Table 18-- steady state flux (J)

[0248] [0248]

Figure CN102670567AD00372

[0249] [0249]

Figure CN102670567AD00381

[0250] *皮肤通量测量结果代表三次测量的平均值和标准偏差。 [0250] * Skin flux measurements represent the average of three measurements and standard deviations.

[0251] **使用人类表皮膜收集的数据 [0251] ** human epidermal membrane using data collected

[0252] _报告的通量测量结果是从累积量对时间曲线的线性区域确定的。 [0252] _ flux measurement report linear region is determined from the time curve of the accumulated amount. 观察到该线性区域处于4-8小时之间。 The linear region was observed between 4-8 hours. 如果实验条件允许,稳态输送可能持续远超过8小时。 If the experiment conditions permit, the steady-state transport is likely to continue far more than eight hours.

[0253] 报告的通量测量结果是从累积量对时间曲线的线性区域确定的。 Flux measurements [0253] reported the cumulative amount from the linear region of the determined time curves. 观察到该线性区域处于6-28小时之间。 The linear region was observed between 6-28 hours. 如果该实验继续,预期稳态也将继续。 If the experiment continues, the expected steady-state will continue.

[0254] 当促通量不挥发溶剂被掺入固化制剂中时,阿昔洛韦、罗哌卡因和睾酮具有令人惊讶地更高的稳态通量值。 [0254] When a flux to promote volatilization of the solvent is not incorporated into the cured formulations, acyclovir, and ropivacaine testosterone has a steady state flux values ​​surprisingly higher. 据推测,较高的通量值可能是挥发性溶剂或凝固剂在固化制剂中影响药物化学环境(如,增加溶解度)而产生较高通量值中的贡献的结果。 Presumably, the higher the flux values ​​or coagulating agent may be a volatile solvent in the chemical environment affect the pharmaceutical formulation curing (e.g., increase solubility) to generate a high flux value of the contribution of the results. 相反地,当促通量不挥发溶剂被掺入固化制剂时,酮洛芬和双氯酚酸具有较低的稳态通量值。 Conversely, when the flux is not promote volatilization of the solvent to be incorporated into cured formulation, ketoprofen and diclofenac have lower steady-state flux values. 这可以是对化学环境具有相反影响(如,降低溶解度,降低药物和制剂间的物理相互作用)而导致较低的通量值的挥发性溶剂系统或凝固剂的结果。 This may have the opposite affect (e.g., reduce the solubility, reduce the physical interaction between the pharmaceutical and formulation) results. The volatile solvent system or a coagulating agent through the lower magnitude of the chemical environment.

[0255] 图I和2分别提供了双氯酚酸和罗哌卡因穿过人尸体皮肤经皮输送的累积量的图示。 [0255] FIGS. I and 2, respectively, provided diclofenac and ropivacaine illustrated cumulants through human cadaver skin is transdermal delivery. 测试的制剂与实施例30和31中所述的类似。 Preparations tested similar to Examples 30 and 31 in the embodiment. 在这些特定的实施方式中,分别在28小时内和30小时内显不出稳态输送。 In these particular embodiments, within 28 hours, respectively, within 30 hours, and nearly as steady state transport.

[0256] 实施例34 [0256] Example 34

[0257] 含有以下组成的固化制剂被应用在肘关节和指关节的人皮肤表面,产生薄的、透明的、柔软且可拉伸的固化层:10. 4%的聚乙烯醇、10. 4%的聚乙二醇400、10. 4%的聚乙烯吡咯烷酮K-90、10. 4%的甘油、27. 1%的水和31. 3%的乙醇。 [0257] cured layer is cured formulation containing the following composition is applied in the elbow joint and a skin surface of a person, resulting in a thin, transparent, flexible and stretchable: 104% polyvinyl alcohol, 10 4. polyethylene glycol 400, 10% of 4% polyvinyl pyrrolidone K-90,10. 4% glycerol, 27.1% water and 31.3% ethanol. 挥发性溶剂(乙醇和水)蒸发数分钟后,形成可剥离的固化层。 Volatile solvents (ethanol and water) after evaporation minutes, forming a cured layer may be peeled off. 所述可拉伸的固化层具有对皮肤的良好粘附性且当弯曲时不会与关节上皮肤分离,而且可以容易地从皮肤上剥离。 The stretchable cured layer with good adhesion to the skin and does not separate from the skin when the joint is bent, and can be easily peeled from the skin.

[0258]实施例 35-37 [0258] Example 35-37

[0259] 与实施例36中制剂类似的三种制剂(用盐酸罗哌卡因(ropivacaine HCl)代替罗哌卡因碱)被应用到刚分离的无毛小鼠皮肤的角质层一侧。 [0259] Example 36 Three formulations similar formulation (ropivacaine hydrochloride (ropivacaine HCl) instead of using ropivacaine base) is applied to the stratum corneum side of the freshly isolated hairless mouse skin. 按照实施例I所述确定每种制剂的体外通量。 I The in vitro flux of each formulation is determined according to an embodiment. 制剂组成列于下面的表19。 Formulation composition shown in Table 19 below.

[0260] 表19 [0260] Table 19

Figure CN102670567AD00382
Figure CN102670567AD00391

[0263] *通量值代表三次测量的平均值和标准偏差。 [0263] Representative flux value * average of three measurements and standard deviations. 报告的通量测量结果是从累积量对时间曲线的线性区域确定的。 Flux measurements reported from the linear region of the cumulative amount versus time curve determined. 观察到该线性区域处于6-31小时之间。 The linear region was observed between 6-31 hours. 如果该实验继续,预期稳态也将继续。 If the experiment continues, the expected steady-state will continue.

[0264] 由于所有三种制剂具有组成完全相同的凝固剂、挥发性溶剂和促通量不挥发溶齐U,唯一的不同是使用了何种促通量不挥发溶剂,因此合理地下结论,对盐酸罗哌卡因来说,Span 20、聚乙二醇400和Tween 40适合作为促通量不挥发溶剂。 [0264] Since all three formulations have identical coagulant composition, the volatile solvent and a nonvolatile solvent to promote homogeneous flux U, the only difference is the use of a flux which is not pro-volatile solvent, to be reasonably concluded, on for ropivacaine, Span 20, Tween 40, polyethylene glycol 400 and not suitable as a flux to promote volatilization of the solvent.

[0265]实施例 38-42 [0265] Example 38-42

[0266] 制备用于皮肤输送咪喹莫特的固化制剂,其包括在赋形剂混合物中的特定量的咪喹莫特,以根据本发明的实施方式形成粘性制剂。 Preparation of [0266] curable formulation for transdermal delivery of imiquimod, excipient mixture which comprises a specific amount of imiquimod, in accordance with embodiments of the present invention is a viscous formulation. 该固化制剂含有以下组分: The cured formulation comprising the following components:

[0267] 表20—咪喹莫特可剥离制剂组分[0268] [0267] Table 20 imiquimod peelable formulation components [0268]

Figure CN102670567AD00392

[0269] *成分按重量百分数表示 [0269] * ingredients in weight percent

[0270] **来自Degussa的聚合物 [0270] ** polymers from Degussa

[0271] 这些制剂按照实施例I所描述被应用到HMS皮肤,并且测定咪喹莫特通量。 [0271] The formulations according to the embodiments described in Example I is applied to the skin HMS, and throughput measuring imiquimod. 用实施例38-42中的制剂进行的体外通量研究的结果汇总列于表21。 The results of in vitro flux studies conducted with formulation examples 38-42 are summarized and tabulated in Table 21.

[0272] 表21_35°C下从各种粘性揭片形成制剂穿过无毛小鼠皮肤的咪喹莫特稳态通量 [0272] From the table 21_35 ° C viscosity of various formulations formed sheet exposing through hairless mouse skin a steady state flux of imiquimod

[0273] [0273]

Figure CN102670567AD00401

[0274] *通量值代表三次测量的平均值和标准偏差(SD) [0274] Representative flux value * average of three measurements and the standard deviation (SD)

[0275] #与对照的比例通过用每个样品的通量值除以艾达乐对照通量的通量值加以计 [0275] # The ratio of the count to be controlled by the magnitude of the control flux through a flux value of each sample divided by the music Ada

Da

ο ο

[0276] 对于实施例38和39中所述的制剂,水被用作挥发性溶剂,而ISA、三乙醇胺混合物被用作不挥发溶剂系统。 [0276] For preparation of Examples 38 and 39 in the embodiment, water is used as the volatile solvent, and the ISA, triethanolamine is used as a nonvolatile solvent mixture system. 通过实验,确定ISA和Span 20为药物提供了适当的溶剂度,但是这些不挥发溶剂是疏水性的并且与用于溶解凝固剂PVA的挥发性溶剂系统不相容。 By experiment, the ISA and Span 20 provides the appropriate degree of drug solvent, these solvents are non-volatile hydrophobic volatile solvent system used to dissolve the coagulant and PVA incompatible. 乳化剂Pemulen TR-2被用于将不挥发溶剂乳化进入水相。 Emulsifier Pemulen TR-2 is used for the non-volatile solvent is emulsified into the aqueous phase. 而且,在这个实施方式中,ISA和三乙醇胺在水(挥发性溶剂)蒸发后在可剥离制剂中发挥增塑剂的作用。 Further, in this embodiment, ISA, and triethanolamine peelable After the water (volatile solvent) was evaporated plasticizer play a role in the formulation. 制剂实施例38和39的稳态通量显示了加入到制剂中的不挥发溶剂的量在控制整个制剂产生通量能力方面的价值。 The steady state flux Formulation Examples 38 and 39 showed an added value to the amount of non-volatile solvent in the formulation to control the entire formulation flux generating capacity. 制剂实施例41和42使用了与非水性挥发性溶剂系统(异丙醇)相容的不同凝固齐U。 Formulation Examples 41 and 42 using a different compatible with the non-aqueous volatile solvent system (isopropanol) solidified homogeneous U. 不挥发溶剂系统ISA/甘油三乙酸酯或ISA/Span 20/三乙醇胺/甘油三乙酸酯组合的选择显示出在体外通量上无变化。 Non-volatile solvent system ISA / triacetin or ISA / Span 20 / triethanolamine / triacetin selected combination exhibits no change in the flux in vitro. 体外通量的上升显示出受到制剂中存在的咪喹莫特量的上升的影响。 In vitro showed increased flux affected by the formulation of imiquimod present in an amount of rise. 在高于4%的咪喹莫特水平下,药物在剥离制剂中是饱和的。 In imiquimod Mott than 4% level, the drug is saturated in the release formulation. 作为药物添加上升的函数的体外通量上升(实施例41和42)可能是由于挥发性溶剂蒸发后药物在固化的剥离制剂中溶解度的增加。 As a function of the drug is added in vitro increased the flux increased (Examples 41 and 42) may be due to increased solubility of the drug after evaporation of volatile solvents in the peeling of the cured formulation.

[0277] 实施例38显示了与其它制剂实施例相当的咪喹莫特通量,以及不挥发溶剂系统和由三乙醇胺的去除引起的凝固剂相容性的值,因为这种不挥发溶剂不利地影响PlastoidB聚合物的功能。 [0277] Example 38 shows an embodiment comparable with the other formulations imiquimod, and the value of compatibility Mott flux from the non-volatile solvent system and the removal of triethanolamine caused coagulant, since such a volatile solvent is not adversely PlastoidB affect the function of the polymer.

[0278]实施例 43-46 [0278] Example 43-46

[0279] 制备用于皮肤输送咪喹莫特的固化制剂,其包括在赋形剂混合物中规定量的咪喹莫特,以根据本发明的实施方式形成粘性制剂。 Preparation of [0279] curable formulation for transdermal delivery of imiquimod, in the excipient mixture comprising a predetermined amount of imiquimod, to form a viscous formulation according to an embodiment of the present invention. 该剥离制剂含有以下组分: The release formulation comprising the following components:

[0280] 表22—咪喹莫特可剥离制剂成分 [0280] Table 22- imiquimod peelable formulation ingredients

Figure CN102670567AD00411

[0282] *成分按重量百分数表示 [0282] * ingredients in weight percent

[0283] **来自Degussa的聚合物 [0283] ** polymers from Degussa

[0284] 这些制剂按照实施例I所描述应用于HMS皮肤,并且测定咪喹莫特通量。 [0284] The formulations according to the embodiments described in Example I is applied to the skin HMS, and throughput measuring imiquimod. 用实施例43-46中的制剂进行的体外通量研究的结果汇总列于表23。 With results of in vitro flux studies of Examples 43-46 are summarized formulations shown in Table 23.

[0285] 表23_35°C下从各种粘性可剥离制剂穿过无毛小鼠皮肤的咪喹莫特稳态通量 [0285] peelable formulation from Table 23_35 ° C under various viscosity through hairless mouse skin a steady state flux of imiquimod

[0286] [0286]

Figure CN102670567AD00412

[0287] *通量值代表三次测量的平均值和标准偏差(SD) [0287] Representative flux value * average of three measurements and the standard deviation (SD)

[0288] #与对照的比例通过用每个样品的通量值除以艾达乐对照通量的通量值加以计 [0288] # The ratio of the count to be controlled by the magnitude of the control flux through a flux value of each sample divided by the music Ada

Da

ο ο

[0289] 实施例43-46的体外通量与艾达乐对照相比得多实质性增加。 [0289] The in vitro flux of embodiment 43-46 and Le Ida substantially increased compared to controls much. 提高的体外通量值的原因可归因于水杨酸的加入。 Cause vitro flux values ​​attributed to an increased addition of salicylic acid. 实施例43-46中提高的咪喹莫特体外咪喹莫特通量被认为是由于咪喹莫特与水杨酸之间的离子对相互作用。 Example 43-46 imiquimod enhanced in vitro imiquimod flux is considered to be due to ion between imiquimod and salicylic acid interactions. 离子对机理被认为是抗衡离子(水杨酸)的亲油性提高了咪喹莫特穿过角质层的通量,因为它使咪喹莫特在该制剂中不太“舒适(comfortable)”。 The mechanism is considered to be ion counterion (salicylic acid) oleophilic imiquimod improved flux through the stratum corneum, as it is unlikely that the imiquimod in the formulation "comfort (Comfortable)." 由于水杨酸而提高通量的另一个原因在于其发挥渗透增强剂的作用。 Another reason is improved since the flux of salicylic acid in its role permeation enhancer. 实施例43-45的通量的比较显示了聚合物和/或挥发性溶剂的选择将影响咪喹莫特的通量。 Comparative Examples 43-45 show embodiments flux selected polymer and / or volatile solvent will affect the flux of imiquimod.

[0290] 实施例47-48 [0290] Example 47-48

[0291] 制备用于皮肤输送罗哌卡因的固化制剂,其包括在赋形剂混合物中规定量的罗哌卡因,以根据本发明的实施方式形成粘性制剂。 Preparation of [0291] curable formulation for transdermal delivery of ropivacaine, which comprises a predetermined amount of ropivacaine excipient mixture, to form a viscous formulation according to an embodiment of the present invention. 该剥离制剂含有以下组分: The release formulation comprising the following components:

[0292] 表24——罗哌卡因剥离制剂成分 [0292] Table 24-- release formulation ingredients ropivacaine

Figure CN102670567AD00421

[0294] *成分以重量百分比表示 [0294] * ingredients expressed in weight percent

[0295] 这些制剂按照实施例I所描述应用于HMS皮肤,并且测定罗哌卡因通量。 [0295] The formulations according to the embodiments described in Example I is applied to the skin HMS, and ropivacaine flux measured. 用实施例47和48中的制剂进行的体外通量研究的结果汇总列于表25。 The results of the flux studies using in vitro and in Formulation Example 48 47 listed in Table 25 are summarized.

[0296] 表25_35°C下从各种粘性可剥离制剂穿过无毛小鼠皮肤的罗哌卡因稳态通量 [0296] peelable formulation from Table 25_35 ° C under various viscosity through hairless mouse skin a steady state flux of ropivacaine

[0297] [0297]

Figure CN102670567AD00422

[0298] *通量值代表三次测量的平均值和标准偏差(SD) [0298] Representative flux value * average of three measurements and the standard deviation (SD)

[0299] 对于实施例47和48中所述的制剂,乙醇被用作挥发性溶剂,而ISA、甘油和PG混合物被用作不挥发溶剂系统。 [0299] For Examples 47 and 48 in the formulation, the ethanol is used as the volatile solvent, and the ISA, a mixture of glycerol and PG are used as non-volatile solvent system. 通过实验,确定ISA和丙二醇一同使用,为药物提供适当的溶剂度,同时与Eudragit RL-100凝固剂相容。 By experiment, the ISA and propylene glycol used together, provide an adequate degree of drug solvent, and is compatible with the coagulant Eudragit RL-100. 而且,在这个实施方式中,ISA、PG和甘油在乙醇(挥发性溶剂)蒸发后在该剥离制剂中发挥增塑剂的作用。 Further, in this embodiment, ISA, PG and glycerin plasticizer play a role in the release formulation in ethanol (volatile solvent) to evaporate. 制剂实施例47和48的罗哌卡因稳态通量显示出不挥发溶剂在控制整个制剂的产生通量能力方面的重要性。 Ropivacaine steady state flux of Formulation Example 47 and 48 show the importance of non-volatile solvent flux generating capacity to control the entire formulation.

[0300] 实施例49 [0300] Example 49

[0301] 溶解度对渗透性、不挥发溶剂系统和凝固剂之间的相容性的影响在本实施例中得以显示。 [0301] solubility in permeability, the compatibility of the non-volatile solvent system and the impact between the coagulating agent to be displayed in the embodiment of the present embodiment. 罗哌卡因碱在异硬脂酸(ISA)中的溶解度被实验确定为稍高于I : 4,意味着I克罗喊卡因喊可以完全溶解在4克异硬脂酸中。 Ropivacaine base solubility isostearic acid (ISA) is slightly higher than the experimentally determined to I: 4, by means Hanka I Crowe call can be completely dissolved in 4 grams of isostearic acid. 在Iv实验中,制备两种溶液:溶液A包含I份罗哌卡因碱和4份异硬脂酸。 In Iv experiment, two solutions were prepared: Solution A containing ropivacaine base parts I and 4 parts of isostearic acid. 溶液B包含I份罗哌卡因碱、4份异硬脂酸和I份三乙醇胺。 Parts of solution B containing ropivacaine base I, 4 parts of isostearic acid and I parts triethanolamine. (所有的份都以重量计)。 (All parts are by weight). 溶液A中的所有罗哌卡因都溶解,但是溶液B中仅有一部分罗哌卡因溶解。 All ropivacaine were dissolved in solution A, solution B, but only a portion of dissolved ropivacaine. 由所述溶液产生的穿过无毛小鼠皮肤的经皮通量通过典型的Franz池系统加以测定,结果如下: Generated by the solution passing through hairless mouse skin by transdermal flux to be measured by a typical Franz cell system, the following results:

[0302] 表26——穿过无毛小鼠皮肤的通量,体外,μ g/h/cm2 [0302] Table 26-- through hairless mouse skin flux, in vitro, μ g / h / cm2

[0303] [0303]

Figure CN102670567AD00431

[0304] 由此可见,溶液B产生的通量是溶液A产生的通量的大约4倍。 [0304] Thus, the flux solution B resulting solution is approximately four times the flux A generated. 这些结果显示了离子配对剂三乙醇胺的加入显著增加了经皮通量。 These results show that the ion pairing agent is added triethanolamine significantly increased the transdermal flux. 然而,将该系统整合进入聚乙烯醇(PVA)基剥离制剂的尝试失败,因为制剂中的PVA发挥了抑制三乙醇胺作用的强pH缓冲的作用。 However, the system is integrated into a polyvinyl alcohol (PVA) based release formulations attempt failed because a PVA formulation plays a strong inhibition effect of triethanolamine pH buffer. 更多三乙醇胺的加入,意图克服PVA的pH缓冲能力,引起期望的PVA固化性质的丧失(换句话说,含有ISA和过多三乙醇胺的不挥发溶剂系统与PVA不相容)。 Lose more triethanolamine was added, pH is intended to overcome the buffering capacity of the PVA, the PVA causing desired curing properties (in other words, ISA and excess triethanolamine containing non-volatile solvent system is incompatible with PVA). 当PVA被另一种凝固剂Eudragit RLlOO (Rohm & Haas)代替,三乙醇胺的影响不被抑制并且获得了能够产生大约30 μ g/h/cm2通量的制剂。 Eudragit RLlOO (Rohm & Haas) was used instead of PVA another coagulant, triethanolamine suppressed and the influence is not capable of producing formulations obtained about 30 μ g / h / cm2 flux. 加入三乙醇胺、ISA和Eudragit RL 100的一个副产物是由三种组分的离子相互作用形成的沉淀。 Triethanolamine, a byproduct of Eudragit RL 100 and ISA are precipitated from the plasma formed by the interaction of three components. 后一实施例在通量和耐磨性方面产生了一种更好的制齐U,但是沉淀仍表明需要改进。 In the latter embodiment generates flux and a better wear resistance made homogeneous U, but still indicate a need to improve the precipitate. 在消除不挥发溶剂与凝固剂之间的离子相互作用的努力中,三乙醇胺、ISA混合物被加入到在异丙醇中的Plastoid B聚合物中。 In efforts to eliminate non-volatile ionic interaction between the solvent and the coagulating agent, triethanolamine, ISA Plastoid B is added to the mixture in the polymer in isopropanol. 然而,在这个例子中,三乙醇胺被发现与Plastoid B聚合物不相容并且该碱被转化为三异丙醇胺。 However, in this example, it was found to be incompatible with triethanolamine Plastoid B and the polymer base is converted to triisopropanolamine. 该组合消除了使用Eudragit RLlOO聚合物时形成的沉淀,并且产生了一种透明制剂,其能够产生大约30 μ g/h/cm2的通量值。 This combination eliminates the precipitate formed when using Eudragit RLlOO polymer, and produce a clear formulation, capable of producing the flux values ​​of about 30 μ g / h / cm2 of. 这显示了不挥发溶剂系统和凝固剂之间相容性的重要性。 This shows the importance of the non-volatile solvent system and between the coagulating agent compatibility.

[0305] 实施例50 [0305] Example 50

[0306] 用以下成分制备皮肤输送罗哌卡因的固化制剂: [0306] curable formulation for transdermal delivery of ropivacaine was prepared using the following ingredients:

[0307] 表27——罗哌卡因固化制剂组分 [0307] Table 27-- cured ropivacaine formulation components

成分* 实施例 Component * Example

[0308] [0308]

Figure CN102670567AD00432

[0309] [0310] *成分以重量份数标注 [0309] [0310] * ingredients in parts by weight are denoted

[0311] 上面所列的成分按照以下程序混合。 The above listed ingredients [0311] mixing the following procedure. Eudragit RL-100与乙醇在玻璃罐中混合并加热到约60°C直到Eudragit RL-100完全溶解。 Eudragit RL-100 were mixed with ethanol in a glass jar and heated to about 60 ° C until complete dissolution of Eudragit RL-100. 当Eudragit溶液冷却到室温时,加入适量盐酸罗哌卡因并充分混合I分钟。 When the Eudragit solution was cooled to room temperature, adding an appropriate amount of hydrochloric acid and mixed thoroughly ropivacaine I min. 向该溶液中加入异硬脂酸(ISA)并且剧烈搅拌该混合物2-3分钟。 To this solution was added isostearic acid (ISA) and the mixture was vigorously stirred for 2-3 minutes. 一小时后,该溶液被再次剧烈混合2-3分钟。 After one hour, the solution was again vigorously mixed for 2-3 minutes. 顺序向该溶液中加入甘油、丙二醇和三乙醇胺。 To this solution was added sequentially glycerol, propylene glycol and triethanolamine. 加入每种成分后,溶液被搅拌I分钟。 After each ingredient was added, the solution was stirred for I min.

[0312] 此外,按照本实施例制备的制剂如实施例I所述被应用到HMS上,并且测定罗哌卡因的通量。 [0312] Furthermore, the preparations prepared according to the present embodiment as described in Example I is applied to the HMS, and ropivacaine measured flux. 结果的汇总列于表28,如下: The results are shown in Table 28 are summarized as follows:

[0313] 表28_35°C下从各种粘性剥离制剂穿过无毛小鼠皮肤的罗哌卡因稳态通量 [0313] TABLE through the 28_35 ° C hairless mouse skin a steady state flux of ropivacaine peeled from a variety of viscous formulations

[0314] [0314]

Figure CN102670567AD00441

[0315] *通量值代表三次测量的平均值和标准偏差 [0315] Representative flux value * average of three measurements and standard deviation

[0316] 按照实施例6制备的罗哌卡因剥离制剂具有可接受的应用特性,例如,从样品管上剥离去除的容易度,在期望的皮肤应用部位涂布的容易性等,并且在正常人类皮肤表面应用厚度约O. Imm的薄层后,在2-3分钟内形成固化膜。 [0316] was prepared according to Example 6 ropivacaine formulation with release embodiment of the acceptable application characteristics, e.g., release the sample tube is removed from the easiness of the coating applied to the skin at the desired site of easiness, and in normal human skin after topical application thickness of from about O. Imm sheet, a cured film is formed within 2-3 minutes. 该固化可剥离层在2小时内变得更容易剥离,而且该剥离层保持粘附于皮肤表面并且该剥离层无任何无意识的去除至少12小时。 The release layer may be cured easier release within 2 hours, and the release layer remains adhered to the skin surface of the release layer and no involuntary removal of at least 12 hours. 期望的使用结束后,该剥离层能够以连续的一片轻易除去。 After the desired use, the release layer can be easily removed in a continuous one.

[0317] 实施例51 [0317] Example 51

[0318] 制备用于皮肤输送利多卡因的固化制剂,其包括在赋形剂混合物中饱和量的利多卡因,以根据本发明的实施方式形成粘性制剂。 Preparation of [0318] the cured formulation for transdermal delivery of lidocaine, in the excipient mixture comprising saturated amount of lidocaine, to form a viscous formulation according to an embodiment of the present invention. 该剥离制剂按照表29中所示的成分制备。 The release formulation was prepared in accordance with components shown in Table 29.

[0319] 表29——利多卡因固化制剂组分 [0319] Table 29-- component curable formulation lidocaine

[0321] [0321]

Figure CN102670567AD00442

[0322] *成分以重量百分比表示 [0322] * ingredients expressed in weight percent

[0323] ** 来自Rohm & Hass [0323] ** from Rohm & Hass

[0324] 表30_35°C下从各种粘性剥离制剂穿过无毛小鼠皮肤的利多卡因稳态通量 [0324] TABLE through the 30_35 ° C hairless mouse skin a steady state flux of lidocaine release from a variety of viscous formulations

[0325] [0325]

Figure CN102670567AD00443

[0326] 本实施例中的粘性可剥离利多卡因制剂具有与上述实施例中的制剂相似的物理性质。 [0326] The embodiment of the present embodiment may be a viscous lidocaine release formulation having the above-described embodiments, the formulation of similar physical properties. 穿过无毛小鼠皮肤的经皮通量是可接受的并且稳态输送可以维持8小时。 Through hairless mouse skin in the transdermal flux steady-state delivery is acceptable and can be maintained for 8 hours.

[0327]实施例 52-55[0328] 制备用于皮肤输送阿米替林和阿米替林与氯胺酮组合的固化制剂,其包括赋形剂混合物,以根据本发明的实施方式形成粘性可剥离制剂。 [0327] Example 52-55 [0328] prepared for transdermal delivery amitriptyline amitriptyline and ketamine curing agents in combination, including excipient mixture thereof, to form a viscous according to an embodiment of the present invention may be peeled off preparation. 该剥离制剂按照表31中所示的成分制备。 The release formulation was prepared in accordance with components shown in Table 31.

[0329] 表31—阿米替林和阿米替林/氯胺酮固化制剂的组分 [0329] Table 31- amitriptyline component and amitriptyline / ketamine curing agents

[0330] [0330]

Figure CN102670567AD00451

[0331] *成分以重量百分比描述 [0331] * composition described in weight percent

[0332] ** 来自DeGussa。 [0332] ** from DeGussa.

[0333] 上面所列的成分按照以下程序混合。 The above listed ingredients [0333] mixing the following procedure. 药物(一种或多种)、水和三异丙醇胺在玻璃罐中混合并混合直到药物溶解。 Drug (s), water and triisopropanolamine are mixed in a glass jar and mixed until the drug is dissolved. 随后,向该制剂中加入异硬脂酸、甘油三乙酸酯、Span 20和异丙醇并充分混合。 Subsequently, the formulation was added to the isostearic acid, triacetin, Span 20 and isopropanol and mixed thoroughly. 聚合物Plastoid B最后加入并加热到约60°C,直到Plastoid B完全溶解。 Plastoid B final polymer was added and heated to about 60 ° C, until completely dissolved Plastoid B. 当聚合物溶液冷却到室温时,该制剂被剧烈搅拌2-3分钟。 When the polymer solution was cooled to room temperature, the formulation was stirred vigorously for 2-3 minutes.

[0334] 表31中的制剂按照实施例I应用到HMS,并测定阿米替林和/或氯胺酮的通量。 In [0334] Table 31. Formulation according to Example I is applied to HMS, and measuring the flux amitriptyline and / or ketamine. 结果总结于表32中: The results are summarized in Table 32:

[0335] 表32_35°C下从各种粘性可剥离制剂穿过无毛小鼠皮肤的阿米替林和阿米替林/ [0335] The following table 32_35 ° C from a variety of tacky peelable formulation through hairless mouse skin amitriptyline and amitriptyline /

氯胺酮稳态通量 Ketamine steady-state flux

[0336] [0336]

Figure CN102670567AD00452

[0337] 本实施例中的阿米替林和阿米替林/氯胺酮配方的粘性可剥离制剂具有与上述实施例中的制剂相似的物理性质。 [0337] In the present embodiment the viscous amitriptyline and amitriptyline / ketamine formulation may release formulations embodiment having the above-described embodiments, the formulation of similar physical properties. 经皮通量与加入到制剂中的药物量成比例。 Transdermal flux added to a pharmaceutical formulation in an amount proportional.

[0338]实施例 56-59 [0338] Example 56-59

[0339] 制备用于皮肤输送罗哌卡因的固化制剂,其包括赋形剂混合物,以根据本发明的实施方式形成粘性剥离制剂。 Preparation of [0339] curable formulation for transdermal delivery of ropivacaine, which comprises a mixture of excipients, to form a viscous release formulation according to an embodiment of the present invention. 该剥离制剂按照表33中所示的成分制备。 The release formulations are prepared according to the ingredients shown in Table 33.

[0340] 表33——盐酸罗哌卡因固化制剂的组分 [0340] ropivacaine, tetracaine hydrochloride Table 33-- curable components of the formulation

Figure CN102670567AD00461
Figure CN102670567AD00462

[0342] *成分以重量份数标注 [0342] * ingredients in parts by weight are denoted

[0343] ** 来自Degussa。 [0343] ** from Degussa.

[0344] 上面所列的成分按照以下程序混合。 The above listed ingredients [0344] mixing the following procedure. 盐酸罗哌卡因、水和三异丙醇胺在玻璃罐中混合并混合直到药物溶解。 Luo ropivacaine hydrochloride, triisopropanolamine water and mixed until the drug is dissolved and mixed in a glass jar. 随后,向该制剂中加入异硬脂酸、甘油三乙酸酯、Span 20和异丙醇并充分混合。 Subsequently, the formulation was added to the isostearic acid, triacetin, Span 20 and isopropanol and mixed thoroughly. 聚合物Plastoid B最后加入并加热到约60°C,直到Plastoid B完全溶解。 Plastoid B final polymer was added and heated to about 60 ° C, until completely dissolved Plastoid B. 当聚合物溶液冷却到室温时,该制剂被剧烈搅拌2-3分钟。 When the polymer solution was cooled to room temperature, the formulation was stirred vigorously for 2-3 minutes.

[0345] 表33中的制剂按照实施例I应用到HMS并,测定罗哌卡因通量。 [0345] Table 33 formulation according to Example I and applied to the HMS, ropivacaine flux measured. 结果总结于表34中: The results are summarized in Table 34:

[0346] 表34_35°C下从各种粘性可剥离制剂穿过无毛小鼠皮肤的盐酸罗哌卡因稳态通量 [0346] peelable formulation from Table 34_35 ° C under various viscosity through hairless mouse skin a steady state flux of ropivacaine

[0347] [0347]

制剂 平均通量mcg/cm2/h * Average flux formulation mcg / cm2 / h *

实施例56 56 + 2 实施例57 39 + 6 实施例58 31 + 6 实施例59 37 + 9 Example 2 Example 56 Example 56 + 6 + 5739 Example 58 embodiment 65 937 + 31 + 9

[0348] 实施例56-59的通量显示了制剂中甘油三乙酸酯、异硬脂酸、Span20组合的重要性。 [0348] Example 56-59 shows the flux formulation triacetin, isostearic acid, combinations Span20 importance. 在实施例56-59中,制剂在分别不含Span20、甘油三乙酸酯和异硬脂酸的情况下制备。 Example 56-59, each formulation prepared in free Span 20, triacetin, and isostearic acid conditions. 罗哌卡因的体外通量受到影响。 Ropivacaine vitro flux affected. 不挥发溶剂的协同组合在获得罗哌卡因最大体外通量方面是重要的。 A synergistic combination of non-volatile solvent is important in obtaining the maximum ropivacaine vitro flux.

[0349] 实施例60 [0349] Example 60

[0350] 固化制剂具有所示重量份数的以下成分: [0350] curable composition having the following formulation shown in parts by weight:

[0351]表 35 [0351] Table 35

[0352] [0352]

Figure CN102670567AD00471

[0353] 在本制剂中,聚乙烯醇(USP级,来自Amresco)是凝固剂,乙基纤维素和Dermacryl79是辅助凝固剂。 [0353] In this formulation, the polyvinyl alcohol (USP grade, from Amresco) a coagulant, ethyl cellulose, and auxiliary Dermacryl79 coagulant. 异硬脂酸和甘油形成不挥发溶剂系统,而乙醇和水形成挥发性溶剂系统。 Isostearic acid and non-volatile solvent system glycerine, ethanol and water formed while the volatile solvent system. 罗喊卡因是药物。 Luo Hanka is due to the drug.

[0354] 制备该制剂的程序: [0354] procedure for the preparation of the formulation:

[0355] I.罗哌卡因与ISA混合。 [0355] I. ropivacaine ISA mixing.

[0356] 2.乙基纤维素和Dermacryl 79溶解在乙醇中。 [0356] 2. Dermacryl 79 and ethylcellulose dissolved in ethanol.

[0357] 3. PVA在约60_70°C的温度下溶解在水中。 [0357] 3. PVA at a temperature of about 60_70 ° C is dissolved in water.

[0358] 4.所有上述混合物在一个容器中一起混合并加入甘油,而且将全部混合物充分混[0359] 产生的制剂是粘稠流体。 [0358] 4. All of the above mixture was mixed in a vessel with glycerin and added, and the entire mixture was mixed thoroughly [0359] formulation produced a viscous fluid. 当约O. Imm厚的一层应用于皮肤上时,在小于2分钟内形成非粘性表面。 When the about O. Imm thick layer applied to the skin, forming a non-tacky surface in less than 2 minutes.

[0360] 实施例61-62 [0360] Example 61-62

[0361] 制备抗真菌固化制剂并且进行剥离片柔软性和粘度的定性评估。 [0361] Preparation of antifungal agents and curing a qualitative assessment of the release sheet flexibility and viscosity. 该制剂的组分列于下面的表36。 The formulation components listed in Table 36 below.

[0362]表 36 [0362] Table 36

Figure CN102670567AD00472

[0364] 实施例61中的剥离制剂具有低粘度,其低于对于在指甲或皮肤表面上应用而言是期望的粘度。 [0364] Formulation Example 61 peel embodiment has a low viscosity, which is lower than for the application on the nail or skin surface in terms of a desired viscosity. 用该制剂形成固化剥离片的时间比期望的干燥时间长。 Time to form a cured release sheet is longer than the formulation with the desired drying time. 实施例62的制剂具有增加的凝固剂(Eudragit RL-P0)量以及减少的乙醇量,这改善了粘度和干燥时间。 Formulation Example 62 has an increased coagulant (Eudragit RL-P0) and the amount of ethanol is reduced, which improves the viscosity and drying time. 实施例62具有适合应用的粘度和改善的干燥时间。 Example 62 and having a viscosity suitable for the application of an improved drying time.

[0365] 实施例63 [0365] Example 63

[0366] 根据表37制备固化制剂,如下: [0366] Table 37 was prepared according to the curable formulation as follows:

[0367] 表37——用于性甾体的成膜制剂 [0367] Table 37-- forming formulations for the sex steroids

[0368] [0368]

Figure CN102670567AD00473
Figure CN102670567AD00481

[0369] 表37的成分按如下混合: Component [0369] Table 37 mixed as follows:

[0370] •凝固剂溶解在挥发性溶剂中(即聚乙烯醇溶解在水中)。 [0370] • coagulant is dissolved in a volatile solvent (i.e., the polyvinyl alcohol dissolved in water).

[0371] •促通量的不挥发溶剂与凝固剂/挥发性溶剂混合物混合。 [0371] • pro flux nonvolatile solvent / volatile solvent mixture mixed coagulating agent.

[0372] •产生的溶液剧烈充分混合数分钟。 Mixed for several minutes with vigorous solution [0372] • generated.

[0373] •随后加入药物并且该膜制剂被再次混合数分钟。 [0373] • followed by addition of the drug formulation and the film is again mixed for several minutes.

[0374] 实施例64 [0374] Example 64

[0375] 测试实施例63中制备的制剂的皮肤通量,如下面表38所述。 [0375] skin flux test formulation prepared in Example 63 in the embodiment, as in Table 38 below.

[0376] 表38——用于性甾体的成膜制剂 [0376] Table 38-- forming formulations for the sex steroids

[0377] [0377]

Figure CN102670567AD00482

[0378] *皮肤通量测量结果代表三次测量的平均值和标准偏差。 [0378] * Skin flux measurements represent the average of three measurements and standard deviations. 报告的通量测量结果是从累积量对时间曲线的线性区域确定的。 Flux measurements reported from the linear region of the cumulative amount versus time curve determined. 该线性区域是在4-8小时之间观察到的。 The linear region is observed between 4-8 hours. 如果实验条件允许,稳态输送可能持续远超过8小时。 If the experiment conditions permit, the steady-state transport is likely to continue far more than eight hours.

[0379] AndroGel,当前市场上的产品,被直接应用在无毛小鼠皮肤并按实施例I所述进行通量确定。 [0379] AndroGel, products currently on the market, without being applied directly press hairless mouse skin in Example I for the determined flux. 稳态通量数据被示于图3中。 Steady-state flux data is shown in Figure 3. 应该注意,表38中报告的稳态通量值是使用2-6小时间的线性区域确定的。 It should be noted, reported in Table 38 using the steady state value is a linear region through a small time determined 2-6. 由图3可见,通过从AndroGel的体外睾酮通量在超过6小时后明显降低。 From in vitro flux AndroGel testosterone significantly reduced by seen in Figure 3, after more than 6 hours. 这可能是部分由于可作为主要输送载体的挥发性溶剂的蒸发。 This may be partly due to the evaporation of the volatile solvent as the main delivery vehicle. 实施例63中的固化制剂将输送稳态量的睾酮至少9小时。 Curing the formulation of Example 63 delivers steady-state testosterone at least 9 hours.

[0380]实施例 65-68 [0380] Example 65-68

[0381] 制备用于经皮输送酮洛芬(其适合通过皮肤输送,用于治疗关节和肌肉的炎症或疼痛)的固化制剂,其包括在赋形剂混合物中饱和量的酮洛芬(比该赋形剂混合物中可溶解的更多的酮洛芬),以形成粘性剥离制剂,其中一部分根据本发明的实施方式制备。 [0381] Preparation for transdermal delivery of ketoprofen (suitable delivery through the skin, muscle and treatment of joint pain, inflammation or a) a cured formulation, which comprises an amount of excipient mixture saturated ketoprofen (ratio the excipient mixture is more soluble ketoprofen), to form a viscous release formulation, wherein a portion of the embodiment of the present invention was prepared in accordance with the embodiment. 所述赋形剂混合物,其是一种粘稠和透明的液体,使用表39中所示的成分加以制备。 The excipient mixture which is a viscous and transparent liquid, ingredients shown in Table 39 to be prepared.

[0382] 表39—酮洛芬固化制剂组分[0384] [0382] Table 39- ketoprofen curable formulation components [0384]

Figure CN102670567AD00491

[0385] *成分以重量百分数表示 [0385] * ingredients expressed in weight percent

[0386] 研究了实施例65-68中每种组合物的酮洛芬通量,显示于表40,如下: [0386] Study of ketoprofen flux of each embodiment of the composition of Example 65-68, shown in Table 40, as follows:

[0387] 表40_35°C下从各种粘性剥离制剂穿过无毛小鼠皮肤的酮洛芬稳态通量 [0387] TABLE through the 40_35 ° C hairless mouse skin a steady state flux of ketoprofen release from a variety of viscous formulations

[0388] [0388]

Figure CN102670567AD00492

[0389] *皮肤通量测量结果代表三次测量的平均值和标准偏差。 [0389] * Skin flux measurements represent the average of three measurements and standard deviations. 报告的通量测量结果是从累积量对时间曲线的线性区域确定的。 Flux measurements reported from the linear region of the cumulative amount versus time curve determined. 该线性区域是在4-8小时之间观察到的。 The linear region is observed between 4-8 hours. 如果实验条件允许,稳态通量将延续至所测量的8小时外。 If the experiment conditions permit the steady state flux will continue to measure the outside for 8 hours.

[0390] 关于实施例65中所述的制剂,乙醇和水形成挥发性溶剂系统,而I : I的甘油和PEG 400混合物形成不挥发溶剂系统。 [0390] Formulation Example 65 regarding the embodiment, the volatile solvent ethanol and water formed in the system, and I: 400 mixture of glycerol and PEG I formed nonvolatile solvent system. 通过实验,确定了对酮洛芬来说PEG 400是比甘油稍好的溶剂,而甘油与PVA的相容性比PEG 400高得多。 By experiment, the solvent for ketoprofen PEG 400 is slightly better than glycerol, glycerol and compatibility with the PVA is much higher than the PEG 400. 因此甘油和PEG400的不挥发溶剂系统一起使用,以为药物提供不挥发溶剂系统,同时与PVA合理地相容。 Thus for use with non-volatile solvent system of glycerol and PEG400, drugs that provide non-volatile solvent systems, while reasonably compatible with the PVA. 有关实施例65的制剂的额外细节中,PVA和PVP发挥凝固剂的作用。 Additional details regarding the formulation of Example 65 of the embodiment, PVA and PVP play a role in the coagulant. 而且,在本实施方式中,甘油和PEG 400也在挥发性溶剂蒸发后形成的粘性可剥离制剂中用作增塑剂。 Further, in the present embodiment, the adhesive 400 is also formed after evaporation of a volatile solvent Glycerol and PEG release formulations may be used as plasticizers. 如果没有甘油和PEG 400的存在,由PVA和PVP单独形成的膜将是刚性且不可拉伸的。 Without the presence of glycerol and PEG 400, a film formed of PVA and PVP alone will be rigid and non-stretchable.

[0391] 关于实施例66的制剂,形成的粘性可剥离制剂具有与实施例65的制剂相似的物理性质,尽管穿过无毛小鼠皮肤的经皮通量更高。 [0391] For the preparation of Example 66, the adhesive forming a peelable formulation with a similar formulation as in Example 65, physical properties, despite a higher through hairless mouse skin in the transdermal flux. 这表明凝固剂、实施例65中的I : IPVA : PVP-K-90和实施例66中的纯PVA,对渗透性有影响。 This indicates coagulant, the I in Example 65: IPVA: PVP-K-90 in Example 66 and pure PVA embodiment, the permeability of the impact.

[0392] 实施例67中的制剂比实施例65或66的制剂输送的酮洛芬少。 [0392] Example 67 formulation in Example embodiments less than 65 or 66 Formulation ketoprofen delivered. 实施例68的制剂比实施例65或66的制剂输送的酮洛芬少得多。 Formulation Example 68 Formulation Example conveyance than 65 or 66 much less ketoprofen. 降低的通量的一个可能的原因被认为是由不挥发溶剂系统中高浓度的PEG 400引起的渗透驱动力的降低,高浓度的PEG 400导致酮洛芬过高的溶解度。 One possible reason for the decrease is considered to reduce the flux, a high concentration of PEG osmotic driving force from the non-volatile solvent system due to a high concentration of PEG 400 400 leads to high solubility of ketoprofen. [0393] 实施例66、67和68的制剂之间唯一的显著差别是关于不挥发溶剂系统,或者更具体地,是PEG 400 :甘油的重量比。 [0393] The only significant difference between the formulation of Examples 66, 67 and 68 embodiment relates to non-volatile solvent system, or, more specifically, PEG 400: glycerin weight ratio. 这些结果反映了不挥发溶剂系统对皮肤通量的影响。 These results reflect the impact of non-volatile solvent system to the skin flux.

[0394] 实施例69 [0394] Example 69

[0395] 制备用于经皮输送利多卡因的可拉伸粘性固化制剂,其包括赋形剂混合物中饱和量的利多卡因,以根据本发明的实施方式形成粘性固化制剂。 Preparation of [0395] viscous curable formulation for the stretchable transdermal delivery of lidocaine, excipient mixture comprising a saturated amount of lidocaine, according to embodiments of the present invention form a viscous curable formulation. 该制剂按照表41中所示的成分制备。 The formulations are prepared according to the ingredients shown in Table 41.

[0396] 表41——利多卡因固化制剂的组分 [0396] Table cured formulation ingredients 41-- Lidocaine

[0397] [0397]

Figure CN102670567AD00501

[0398] *成分以重量份数表示 [0398] * ingredients expressed in parts by weight

[0399] ** 来自Rohm & Hass [0399] ** from Rohm & Hass

[0400] 表42_35°C下从粘性固化制剂穿过无毛小鼠皮肤的利多卡因稳态通量 [0400] TABLE through the 42_35 ° C hairless mouse skin a steady state flux of lidocaine from the adhesive cured formulation

[0401] [0401]

Figure CN102670567AD00502

[0402] *皮肤通量测量结果代表三次测量的平均值和标准偏差。 [0402] * Skin flux measurements represent the average of three measurements and standard deviations. 报告的通量测量结果是从累积量对时间曲线的线性区域确定的。 Flux measurements reported from the linear region of the cumulative amount versus time curve determined. 该线性区域是在4-8小时之间观察到的。 The linear region is observed between 4-8 hours. 如果实验条件允许,稳态通量可能在超过测量的8小时后继续。 If the experiment conditions permit the steady state flux may continue after exceeding measured for 8 hours.

[0403] 本实施例中的利多卡因的粘性固化制剂具有与实施例65-68中制剂相似的物理性质。 [0403] In the present embodiment the viscous curable formulation has the lidocaine embodiment similar to the embodiment of the physical properties of the formulation 65-68. 穿透无毛小鼠皮肤的透皮通量是可接受的并且稳态输送保持超过8小时。 Hairless mouse skin penetration flux transdermal delivery is acceptable and held steady over 8 hours.

[0404] 实施例70 [0404] Example 70

[0405] 与实施例65的组合物制剂类似的制剂(不含酮洛芬)被应用于肘关节和指关节处的人皮肤表面,形成一层薄的、透明的、柔软且可拉伸的膜。 [0405] with the composition similar to the formulation of Example 65 formulation (excluding ketoprofen) is applied to the skin surface of a person and elbow joints, forming a thin, transparent, flexible and stretchable membrane. 挥发性溶剂(乙醇和水)蒸发数分钟后,形成固化可剥离层。 Volatile solvents (ethanol and water) after evaporation minutes to form a cured peelable layer. 所述可拉伸膜具有良好的皮肤粘着性且弯曲时不会从皮肤上分离,而且可以容易地从皮肤上剥离。 The stretched film can have good skin when the skin is not detached from the adhesion and bent, and can be easily peeled from the skin.

[0406]实施例 71-73 [0406] Example 71-73

[0407] 制备用于经皮输送酮洛芬(其适合经由关节和肌肉上的皮肤的输送)的可拉伸粘性固化制剂,其包括在赋形剂混合物中饱和量的酮洛芬(比该赋形剂混合物中可溶解的更多的酮洛芬),以形成粘着可剥离制剂,其中一部分根据本发明的实施方式制备。 [0407] Preparation for transdermal delivery of ketoprofen (which is adapted to deliver a skin over the joints and muscles through) stretchable viscous curable formulation comprising ketoprofen saturated amount of the excipient mixture (the ratio more soluble in the excipient mixture ketoprofen), to form a peelable adhesive formulations prepared according to embodiment wherein a portion of the embodiment of the present invention. 所述赋形剂混合物,一种粘稠和透明的液体,使用表43中所示的成分制备。 The excipient mixture, a viscous and transparent liquid, prepared from the ingredients shown in Table 43.

[0408]表 43 [0408] Table 43

[0409] [0409]

Figure CN102670567AD00511

[0410] 实施例71-73的剥离制剂以如下方式制备: Release formulations [0410] Example 71-73 was prepared in the following manner:

[0411] •凝固剂溶解于挥发性溶剂中(即在乙醇中溶解Eudragit聚合物)。 [0411] • setting agent is dissolved in a volatile solvent (i.e., Eudragit polymer is dissolved in ethanol).

[0412] •通量足够的不挥发溶剂(甘油、PEG)与凝固剂/挥发性溶剂混合物一起混合。 [0412] • flux sufficient non-volatile solvent (glycerol, PEG) were mixed together with a coagulating agent / volatile solvent mixture.

[0413] •产生的溶液被剧烈混合数分钟。 Solution [0413] • are produced vigorously mixed for several minutes.

[0414] •药物随后被加入并且该制剂被再次混合数分钟。 [0414] • medicament is then added and the formulation was again mixed for several minutes.

[0415] 实施例74 [0415] Example 74

[0416] 根据实施例71-73制备的制剂按照实施例I所述应用到HMS,并测定酮洛芬通量。 [0416] Example I in accordance with the formulations prepared according to Examples 71-73 the application embodiment of the HMS, and ketoprofen flux was measured. 结果的汇总列于表44,如下: The results are shown in Table 44 are summarized as follows:

[0417] 表44—酮洛芬穿过无毛小鼠皮肤的稳态通量 [0417] Table 44 Ketoprofen through hairless mouse skin a steady state flux

[0418] [0418]

Figure CN102670567AD00512

[0419] *皮肤通量测量结果代表三次测量的平均值和标准偏差。 [0419] * Skin flux measurements represent the average of three measurements and standard deviations. 报告的通量测量结果是从累积量对时间曲线的线性区域确定的。 Flux measurements reported from the linear region of the cumulative amount versus time curve determined. 该线性区域是在4-8小时之间观察到的。 The linear region is observed between 4-8 hours. 如果实验条件允许,稳态通量可能在超过测定的8小时后继续。 If the experiment conditions permit the steady state flux may continue after exceeding measured for 8 hours.

[0420] 根据实施例71-72制备的酮洛芬制剂具有可接受的固化层性质(如,在2-3分钟内形成固化层)。 [0420] The ketoprofen formulations prepared in Example 71-72 embodiment having acceptable properties of the cured layer (e.g., a solidified layer is formed within 2-3 minutes). 用实施例73,酮洛芬揭片在应用后30分钟不形成固化层。 Of Example 73, ketoprofen sheet 30 minutes without exposing the solidified layer formed after applying. 这表明为了在剥离制剂中获得理想的通量和耐磨性,在开发制剂时应评价并考虑凝固剂、不挥发溶剂和挥发性溶剂间微妙的平衡。 This indicates that in order to obtain the desired release formulation fluxes and wear resistance, evaluated and considered coagulant, a delicate balance between the non-volatile solvent and the volatile solvent in the formulation should be developed.

[0421] 实施例75 [0421] Example 75

[0422] 制备用于透皮输送酮洛芬(其适合经由关节和肌肉上皮肤的输送)的可拉伸粘性固化制剂,其包括在赋形剂混合物中饱和量的酮洛芬(比该赋形剂混合物中可溶解的更多的酮洛芬),以形成粘性可剥离制剂,其中一部分根据本发明的实施方式制备。 Stretchable viscous curable formulation, which comprises ketoprofen in a saturating amount of the excipient mixture prepared in [0422] for transdermal delivery of ketoprofen (via suitable conveying joints and skin muscle) (the ratio fu shaped mixture in the more soluble ketoprofen), to form a viscous formulation can be peeled off, some of which were prepared according to embodiments of the present invention. 所述赋形剂混合物,一种粘稠和透明的液体,使用表45中所示的成分制备。 The excipient mixture, a viscous and transparent liquid, prepared from the ingredients shown in Table 45.

[0423]表 45 [0423] TABLE 45

Figure CN102670567AD00521

[0425] *成分以重量百分数表示 [0425] * ingredients expressed in weight percent

[0426] 制剂A和B按如下方式制备: [0426] Formulations A and B prepared as follows:

[0427] · PVA (凝固剂)溶解在水中。 [0427] · PVA (coagulant) was dissolved in water.

[0428] •通量足够的不挥发溶剂(甘油、PG)与凝固剂/挥发性溶剂混合物一起混合。 [0428] • flux sufficient non-volatile solvent (glycerol, PG) were mixed together with a coagulating agent / volatile solvent mixture.

[0429] •随后,乙醇和Gantrez ES 425被加入到该混合物中。 [0429] • Subsequently, ethanol, and Gantrez ES 425 is added to the mixture.

[0430] •产生的溶液被剧烈混合数分钟。 Solution [0430] • are produced vigorously mixed for several minutes.

[0431] 制剂C中PVA水溶液的制备对于该分子量的PVA在所标注的百分比下不可行。 [0431] Formulation C is prepared in an aqueous solution of PVA to the molecular weight of the PVA is not feasible at the marked percentage. 制剂C显示了正确的PVA聚合物分子量对获得理想的制剂性质是重要的。 Formulation C shows the correct molecular weight of the PVA polymer is important to achieve the desired formulation properties.

[0432] 制剂A和B被置于人类志愿者的皮肤上。 [0432] Formulations A and B are placed on the skin of human volunteers. 在对于挥发性溶剂蒸发足够长的若干小时后,志愿者除去剥离片并评估其可剥离性。 After evaporation several hours long enough for the volatile solvent, removing the release sheet volunteers and evaluated for peelability. 在所有的情况下,志愿者报告,制剂实施例A无法以一或两片除去,但以许多小块除去。 In all cases, the volunteers reported, Formulation Example A could not be removed in one or two, but in many small pieces removed. 制剂实施例B以一或两片除去。 Formulation Example B to remove one or two. 制剂A的脆性归因于较低分子量的PVA样品(Celvol)。 Formulation A brittle sample due to the relatively low molecular weight PVA (Celvol). 低分子量PVA不具有与较高分子量PVA材料(Amresco)相同的内聚力(cohesive strength),这是由于聚合链降低的大小导致各个PVA聚合物链之间交联程度和物理相互作用的降低。 Low molecular weight PVA PVA does not have a higher molecular weight material (Amresco) same cohesive force (cohesive strength), which is due to the reduced size of the polymeric chain results in reduced cross-linking degree and physical interaction between the various PVA polymer chains. 降低的PVA链相互作用导致变弱的剥离片,其无法承受去除时剥离片经受的机械力。 PVA chain interaction results in a reduced weakened release sheet, the release sheet is subjected to mechanical forces which can not afford the time of removal.

[0433] 实施例76 [0433] Example 76

[0434] 评价用于经皮输送酮洛芬(其适合经由关节和肌肉上的皮肤进行输送)的可拉伸粘性固化制剂,其包括赋形剂混合物,所述赋形剂混合物将形成粘性可剥离制剂,其中一部分根据本发明的实施方式制备。 [0434] Evaluation of stretchable adhesive solidifying formulations for transdermal delivery of ketoprofen (which is suitable for delivery via the skin, muscle and joints), which comprises a mixture of an excipient, the excipient can form a viscous mixture release formulation, wherein a portion of the embodiment of the present invention was prepared in accordance with the embodiment. 所述赋形剂混合物,一种粘稠和透明的液体,使用表46中所示的成分制备。 The excipient mixture, a viscous and transparent liquid, was prepared using the ingredients shown in Table 46.

[0435] 表46[0436] [0435] Table 46 [0436]

Figure CN102670567AD00531

[0437] *成分以重量百分数标注 [0437] * ingredients in weight percent are denoted

[0438] 制剂DG中的剥离制剂按如下方式制备: [0438] DG release preparations which are prepared as follows:

[0439] · PVA (凝固剂)溶解在水中。 [0439] · PVA (coagulant) was dissolved in water.

[0440] •通量足够的不挥发溶剂(甘油、PG)与凝固剂/挥发性溶剂混合物一起混合。 [0440] • flux sufficient non-volatile solvent (glycerol, PG) were mixed together with a coagulating agent / volatile solvent mixture.

[0441] •随后,乙醇和Gantrez ES 425被加入到该混合物中。 [0441] • Subsequently, ethanol, and Gantrez ES 425 is added to the mixture.

[0442] •产生的溶液被剧烈混合数分钟。 Solution [0442] • are produced vigorously mixed for several minutes.

[0443] •混合后,酮洛芬被加入并且最终混合物被再次剧烈混合数分钟。 [0443] • After mixing, ketoprofen was added and the final mixture is again mixed vigorously for several minutes.

[0444] 上述制剂被置于多层式包装管(laminated packaging tube)中并储存在25°C /60% RH和40°C /75% RH的条件下直到取出测试。 [0444] The preparation is placed in a multi-layered packaging tubes (laminated packaging tube) and stored at 25 ° C / 60% RH and 40 ° C / 75% RH until the extraction test. 对每种制剂进行物理测试。 Physical testing of each formulation. 制剂DF已经被研究了最长的时间并且产生的粘度增加使研究制剂G粘度的要求成为必要。 DF formulation has been studied the longest and the resulting increase in viscosity making the formulation studies G viscosity requirements necessary. 表47汇总了每种制剂产生的数据。 Table 47 summarizes the data generated for each formulation.

[0445]表 47 [0445] Table 47

[0446] [0446]

Figure CN102670567AD00532

[0447] [0447]

Figure CN102670567AD00541
Figure CN102670567AD00542

[0448] *使用RVDV 1+粘度计在O. 5rpm下测量的粘度 [0448] * using the viscometer RVDV 1+ 5rpm viscosity measured O.

[0449] 本实施例的制剂D和E具有四种制剂中最低的水含量并且在4周的储存中达到高粘度值。 [0449] Formulation D and E of the present embodiment has the lowest four formulations to achieve high water content and viscosity values ​​at 4 weeks storage. 制剂I和2之间唯一的不同是制剂中乙醇的量。 Formulation I and the only difference between the two is the amount of ethanol in the formulation. 假设降低乙醇的量可降低制剂的物理稠化,这是由于PVA和乙醇之间的不相容性。 Suppose reduce the amount of ethanol may reduce the physical thickening agents, due to the incompatibility between the PVA and ethanol. 粘度数据显示较高乙醇含量的制剂(制剂D)具有较低的初始粘度,但是4周储存之后制剂D和E的粘度都达到对于可用制剂过高的粘度值。 The viscosity data show that the higher alcohol content of the formulation (formulation D) has a lower initial viscosity, but after storage for 4 weeks Formulation D and E have reached a viscosity of excessively high viscosity values ​​can be used for the formulation. 制剂稠化的另一个假设是当溶于水时,PVA在高浓度下不相容。 Another assumption is thickened formulation when dissolved in water, PVA is incompatible at high concentrations. 制备含有较高水含量的其它制剂,以确定最优化的水含量是否将保持制剂不随时间增稠。 Other formulations prepared containing higher water content, in order to determine whether to optimize the water content remains constant over time thickened formulation. 制剂F在16周后的粘度未能达到制剂I和2的初始粘度值的粘度值。 Formulation F Viscosity after 16 weeks failed to meet the initial viscosity of the formulation viscosity values ​​I and 2.

[0450] 上述制剂的空白对照版本被应用于研究志愿者并通过将一片棉花置于应用部位且随后在棉花上应用5克重来评估干燥时间。 [0450] placebo version of the above formulation was applied by a study of volunteers and cotton and then placed in the site of application on the application weight of 5 g of cotton to evaluate the drying time. 5秒后棉花和重量被除去。 By weight of cotton and is removed after 5 seconds. 这一过程开始于应用后约3-4分钟并在之后以10-60秒的间隔进行,直到棉花被移除而没有带起剥离片或留下残留物。 The process begins at about 3-4 minutes after application and followed by an interval of 10-60 seconds until the tape without the release sheet from the cotton is removed or leave a residue. 研究的结果总结于下面的表48。 Results of the study are summarized in Table 48 below.

[0451]表 48 [0451] Table 48

[0452] [0452]

制剂I干燥时间(分钟Γ^ Formulation I Drying time (minutes Γ ^

~ 4分49秒~ 5分41秒~ 4分27秒~~ G 5分I秒 ~ 4 minutes 49 seconds to 5 minutes and 41 seconds to 4 minutes and 27 seconds seconds I ~~ G 5 minutes

[0453][0454] *12位研究受试者的平均干燥时间 The average drying time [0453] [0454] * 12 subjects Study

[0455] 乙醇作为第二挥发性溶剂的存在似乎明显缩短了干燥时间。 [0455] the presence of ethanol as a second volatile solvent appears significantly shorten the drying time. 在未示出的数据中,仅含水作为挥发性溶剂并且水与PVA比例为2 : I的局部麻醉制剂具有> 15分钟的干燥时间。 In data not shown, only water as a volatile solvent and water to PVA ratio of 2: I formulation with a local anesthetic> drying time of 15 minutes. 优化比例以及含水制剂中额外挥发性溶剂的存在显著缩短了干燥时间。 Optimization of the ratio and the presence of additional aqueous formulation of volatile solvents significantly reduces the drying time. 假设额外的挥发性溶剂一在该情况下为乙醇一将与水形成氢键,并且当从皮肤上蒸发时,水与乙醇一同挥发,从而形成固化揭片。 Suppose eleven additional volatile solvent will form in this case water, ethanol and hydrogen, and when evaporating from the skin with water and ethanol, volatile, exposing to form a cured sheet.

[0456]实施例 77-79 [0456] Example 77-79

[0457] 制备用于皮肤输送盐酸罗哌卡因的固化制剂,其包括依据本发明实施方式的赋形剂混合物。 Preparation of [0457] curable formulation for transdermal delivery of ropivacaine, which comprises the excipient mixture according to an embodiment of the present invention. 所述制剂按照表49中所示成分制备。 The formulations are prepared according to the composition shown in Table 49.

[0458] 表49——盐酸罗哌卡因固化制剂的组分 [0458] ropivacaine, tetracaine hydrochloride Table 49-- curable components of the formulation

Figure CN102670567AD00551

[0460] *成分以重量百分比标注 [0460] * ingredients in weight percent are denoted

[0461] ** 来自Degussa。 [0461] ** from Degussa.

[0462] 上述成分按照以下程序混合。 [0462] The components were mixed according to the following procedure. 盐酸罗哌卡因、水和胺碱(三乙胺或二异丙醇胺)在玻璃罐中结合并混合直到药物溶解。 Luo ropivacaine hydrochloride, water and an amine base (triethylamine or di-isopropanol amine) are combined and mixed until the drug is dissolved in a glass jar. 随后向该制剂中加入异硬脂酸、甘油三乙酸酯、Span20和十六烷醇(实施例78和79)或异丙醇(实施例77)并充分混合。 To this formulation was added followed isostearic acid, triacetin, cetyl alcohol and Span 20 (Examples 78 and 79) or isopropanol (Example 77) was added and mixed well. 聚合物Plastoid B最后加入并加热到约60°C直到Plastoid B完全溶解。 Plastoid B final polymer was added and heated to about 60 ° C until complete dissolution Plastoid B. 该聚合物溶液冷却到室温时,该制剂被剧烈搅拌2-3分钟。 When the polymer solution was cooled to room temperature, the formulation was stirred vigorously for 2-3 minutes.

[0463] 表49中的制剂按照实施例I应用到HMS并测量罗哌卡因的通量。 [0463] Table 49 formulation according to Example I and applied to the measurement HMS ropivacaine flux. 结果汇总于表50 : The results are summarized in Table 50:

[0464] 表50_35°C下从各种粘性固化制剂穿过无毛小鼠皮肤的盐酸罗哌卡因稳态通量 [0464] TABLE through the 50_35 ° C hairless mouse skin a steady state flux of ropivacaine hydrochloride from a variety of adhesive solidifying formulation

[0465] [0465]

Figure CN102670567AD00552
Figure CN102670567AD00561

[0466] 尽管本发明参考某些优选的实施方式进行了描述,但是本领域的普通技术人员将理解,各种修改、变化、省略和替代可以在不背离本发明精神的情况下进行。 [0466] Although the present invention with reference to certain preferred embodiments have been described, those of ordinary skill in the art will appreciate that various modifications, changes, omissions and substitutions may be made without departing from the spirit of the invention. 因此,本发明意图仅被所附的权利要求书的范围所限制。 Accordingly, the present invention is intended by the appended claims only by the scope of the restrictions.

Claims (22)

1.用于皮肤输送药物的制剂,其包括: a)药物; b)溶剂载体,包含: i)挥发性溶剂系统,包括至少一种挥发性溶剂,和ii)不挥发溶剂系统,其对所述药物是促通量的,以便所述药物在一段时间内以治疗有效量被输送;以及c)凝固剂,其在所述挥发性溶剂系统至少部分蒸发后有助于应用于皮肤表面的所述制剂层的固化, 其中,所述制剂具有适合应用并且在所述挥发性溶剂系统蒸发前粘附在所述皮肤表面的粘度,并且其中应用于所述皮肤表面的所述制剂在所述挥发性溶剂系统至少部分蒸发后形成固化可剥离层而没有背层,其中所述药物在所述挥发性溶剂系统至少基本蒸发后继续被输送。 1. The skin preparations for delivery of a drug, which comprises: a) a drug; b) a solvent carrier, comprising: i) a volatile solvent system comprising at least one volatile solvent, and ii) a non-volatile solvent system to the said pharmaceutical is a pro-flux, so that the medication is delivered in a therapeutically effective amount over a period of time; and c) a coagulating agent, which facilitates the application to the skin surface after at least partial evaporation of the volatile solvent system cured layer of said formulation, wherein said formulation suitable for use and having prior to evaporation of the volatile solvent system in the viscosity of the adhesive surface of the skin, is applied to the skin surface and wherein said formulation in said volatilization the solvent system may be formed of a cured release layer without the backing layer is at least partially evaporated, wherein the medicament continues to be conveyed after the volatile solvent system is at least substantially evaporated.
2.如权利要求I中的制剂,其中所述不挥发溶剂系统是用于所述凝固剂的增塑剂。 The formulation I as claimed in claim 2, wherein said plasticizer is a non-volatile solvent system for said coagulant.
3.如权利要求I中的制剂,其中所述不挥发溶剂系统包含至少两种不挥发溶剂并且所述不挥发溶剂系统能够产生比每种不挥发溶剂各自产生的更高的所述药物的皮肤通量。 3. The formulation of claim I, wherein said non-volatile solvent system comprises at least two non-volatile solvent and the non-volatile solvent system can produce a higher ratio of drug to the non-volatile solvent in each respective resulting skin flux.
4.如权利要求I中的制剂,其中所述制剂进一步包含额外的试剂,其被包括在内,以在应用于所述皮肤表面时增加所述制剂的粘附性。 The formulation I as claimed in claim 4, wherein said formulation further comprises additional agents, which are included to increase the adhesion of the formulation, when applied to the skin surface.
5.如权利要求I中的制剂,其中所述挥发性溶剂系统包含水和/或至少一种比水更具挥发性的溶剂,并包括选自下列的至少一种:乙醇、异丙醇、水、二甲醚、二乙醚、丁烷、丙烷、异丁烯、I, I-二氟乙烷、I, I, I, 2-四氟乙烷、1,1,1,2,3,3,3-七氟丙烷、1,1,1,3,3,3-六氟丙烷、乙酸乙酯、和丙酮、变性酒精、甲醇、丙醇、异丁烯、戊烷、己烷、甲基•乙基酮、丁醇、丁醇、乙酰单甘油酯、烷基二氧戊环、香菜油、环甲基硅酮、二甘醇一乙醚、牛奶、橄榄醇、乙酸乙烯酯、己烯甘油、甲基丙烯酸、和它们的组合。 5. The formulation of claim I, wherein the volatile solvent system comprises water and / or at least one solvent more volatile than water, and includes at least one selected from the group consisting of: ethanol, isopropanol, water, dimethyl ether, diethyl ether, butane, propane, isobutene, I, I- difluoroethane, I, I, I, 2- tetrafluoroethane, 1,1,1,2,3,3, 3- heptafluoropropane, 1,1,1,3,3,3-hexafluoropropane, ethyl acetate, acetone, denatured alcohol, methanol, propanol, isobutene, pentane, hexane, methyl ethyl ketone •, , butanol, acetylated monoglyceride, alkyl dioxolane, coriander oil, cyclomethicone, diethylene glycol monoethyl ether, milk, olive alcohol, vinyl acetate, hexene glycerol, methacrylic acid, and combinations thereof.
6.如权利要求I中的制剂,其中所述促通量不挥发溶剂系统在所述药物单独存在于所述不挥发溶剂系统中时,为所述药物提供至少两倍于达到治疗有效通量所需的通量。 6. A formulation as claimed in claim I, wherein said non-volatile solvent system to promote the flux of the medicament when present alone in said non-volatile solvent system, to provide at least twice the medicament to achieve a therapeutically effective flux the required flux.
7.如权利要求I的制剂,其中所述不挥发溶剂系统包括一种或多种选自下列的溶剂:·1,2,6-己三醇、烷三醇、烷二醇、生育酚、对丙烯基茴香醚、茴香油、杏仁油、二甲基异山梨醇、烷基葡糖苷、苯甲醇、蜂蜡、苯甲酸苄酯、丁二醇、辛酸/癸酸甘油三酯、焦糖、山扁豆油、蓖麻籽油、肉桂醛、肉桂油、丁香油、椰子油、可可脂、椰子甘油酯、玉米油、芫荽油、玉米糖浆、棉籽油、甲酚、二醋精、二乙酰单甘油酯、二乙醇胺、甘油二酯、乙二醇、桉树油、脂肪、月旨肪醇、香料、液体糖、生姜提取物、甘油、高果糖玉米糖浆、氢化蓖麻油、IP棕榈酸酯、柠檬油、白柠檬油、苧烯、一醋精、甘油单酯、肉豆蘧油、辛基十二烷醇、甜橙油、棕榈油、花生油、PEG植物油、薄荷油、凡士林油、苯酚、松针油、聚丙二醇、芝麻油、留兰香油、大豆油、植物油、植 7. The formulation of claim I, wherein said non-volatile solvent system comprises one or more solvents selected from the group consisting of: * 1,2,6-triol alkyl, alkylene glycol, tocopherol, on anethole, anise oil, apricot oil, dimethyl isosorbide, alkyl glucoside, benzyl alcohol, bees wax, benzyl benzoate, butylene glycol, caprylic / capric triglyceride, caramel, mountain flat soybean oil, castor oil, cinnamaldehyde, cinnamon oil, clove oil, coconut oil, cocoa butter, coco-glycerides, corn oil, coriander oil, corn syrup, cottonseed oil, cresol, diacetin, diacetylated monoglyceride esters, diethanolamine, diglycerides, ethylene glycol, eucalyptus oil, fat, fatty alcohols purpose month, flavors, liquid sugars ginger extract, glycerin, high fructose corn syrup, hydrogenated castor oil, the IP palmitate, lemon oil , lime oil, limonene, a triacetin, monoglycerides, Qu nutmeg oil, octyldodecanol, sweet orange oil, palm oil, peanut oil, PEG vegetable oil, peppermint oil, petrolatum, phenol, pine needle oil , polyethylene glycol, sesame oil, spearmint oil, soybean oil, vegetable oil, plant 油制起酥油、蜡、2-(2-(十八烷氧基)乙氧基)乙醇、苯甲酸苄酯、丁基化羟基苯甲醚、小烛树蜡、巴西棕榈蜡、鲸蜡硬脂醇聚醚-20、十六烷醇、聚甘油、二聚羟基硬脂酸酯、PEG-7氢化蓖麻油、邻苯二甲酸二乙酯、癸二酸二乙酯、二甲基硅氧烷、邻苯二甲酸二甲酯、PEG脂肪酸酯、PEG-硬脂酸酯、PEG-油酸酯、PEG-月硅酸酯、PEG脂肪酸二酯、PEG- 二油酸酯、PEG- 二硬脂酸酸酯、PEG-蓖麻籽油、山嵛酸甘油酯、PEG甘油脂肪酸酯、PEG月桂酸甘油酯、PEG硬脂酸甘油酯、PEG油酸甘油酯、羊毛脂、月桂酸二乙醇胺、月桂乳酸酯、月桂硫酸酯、亚甲磷酸、多留醇提取物、肉豆蘧醇、中性油、PEG-辛基苯基醚、PEG-烷基醚、PEG-十六烷基醚、PEG-十八烷基醚、PEG-失水山梨糖醇脂肪酸酯、失水PEG-山梨糖醇二异硬脂酸酯、PEG-失水山梨糖醇单硬脂酸酯、丙二醇脂肪酸酯、丙二醇硬脂酸 Shortening system oil, wax, 2- (2- (octadecyloxy) ethoxy) ethanol, benzyl benzoate, butylated hydroxyanisole, candelilla wax, carnauba wax, spermaceti hard -20 aliphatic polyether alcohols, cetyl alcohol, polyglyceryl, dipolyhydroxy stearate, PEG-7 hydrogenated castor oil, diethyl phthalate, diethyl sebacate, dimethyl silicone dioxane, dimethyl phthalate, PEG fatty acid esters, PEG- stearate, PEG- oleate, PEG- month silicate, PEG fatty acid diesters, PEG- dioleate, PEG- two stearic acid esters, PEG- castor oil, glyceryl behenate, PEG glycerol fatty acid esters, PEG glyceryl laurate, PEG glyceryl stearate, PEG glyceryl oleate, lanolin, lauric acid ethanolamine, lauryl lactate, lauryl sulfate, methylenedioxy acid, leaving alcohol extract, nutmeg Qu alcohol, neutral oil, PEG- octylphenyl ether, PEG- alkyl ethers, PEG- cetyl ether , PEG- stearyl ether, PEG- sorbitan fatty acid esters, sorbitan PEG- sorbitan diisostearate, PEG- sorbitan sorbitan monostearate, propylene glycol fatty acid esters, propylene glycol stearate 、丙二醇、辛酸酯/癸酸酯、吡咯烷酮羧酸钠、山梨醇、三十碳六烯、stear-o-wet、甘油三酯、烷基芳基聚醚醇、失水山梨糖醇醚的聚氧乙烯衍生物、饱和的聚乙二醇化的C8-C10甘油酯、N-甲基吡咯烷酮、蜂蜜、聚氧乙基化甘油酯、二甲亚砜、氮酮及相关化合物、二甲基甲酰胺、N-甲基甲酰胺、脂肪酸酯、脂肪醇醚、烷基酰胺(N,N-二甲基烷基酰胺)、N-甲基吡咯烷酮相关化合物、油酸乙酯、聚甘油化脂肪酸、单油酸甘油酯、单肉豆蘧酸甘油酯、脂肪酸的甘油酯、丝氨基酸、PPG-3苯甲醚肉豆蘧酸酯、二-PPG2肉豆蘧醇聚醚10-己二酸酯、honeyquat、焦谷氨酸钠、海甘蓝油、二甲基硅氧烷、澳洲坚果油、绣线菊籽油、鲸蜡硬脂醇、PEG-50牛油树脂、牛油树脂、芦荟汁、苯基三甲基硅氧烷、水解的小麦蛋白、甘油、油酸、三乙醇胺、氨丁三醇、甘油三乙酸酯、失水山梨 , Propylene glycol, caprylate / caprate, sodium pyrrolidone carboxylate, sorbitol, squalene, stear-o-wet, triglycerides, alkyl aryl polyether alcohols, sorbitan ethers polyoxyethylene derivatives, saturated polyglycolized glycerides of C8-C10, N- methylpyrrolidone, honey, polyoxyethylated glycerides, dimethyl sulfoxide, azone and related compounds, dimethylformamide, amides, N- methyl formamide, fatty acid esters, fatty alcohol ethers, alkyl-amides (N, N- dimethyl-alkylamide), N- methylpyrrolidone related compounds, ethyl oleate, polyglycerol fatty acid , glyceryl monooleate, glyceryl mono myristoyl Qu triglyceride of fatty acids, silk amino acids, PPG-3 anisole myristoyl Qu, di- -PPG2 myristoyl Qu laureth adipate 10- , honeyquat, sodium pyroglutamate, crambe oil, dimethicone, macadamia nut oil, meadowfoam seed oil, cetearyl alcohol, PEG-50 shea butter, shea butter, aloe vera juice, phenyl trimethicone, hydrolyzed wheat protein, glycerol, oleate, triethanolamine, tromethamine, triacetin, sorbitan 醇单月桂酸酯、失水山梨糖醇单油酸酯、失水山梨糖醇单棕榈酸酯、苯甲酸、癸二酸二丁酯、甘油二酯、双丙甘醇、丁子香酚、脂肪酸、十四酸异丙酯、矿物油、油醇、维生素E、甘油三酯、失水山梨糖脂肪酸酯表面活性剂、柠檬酸三乙酯、乙酸异戊酯、氯丁醇、松节油、环五硅氧烷、环甲基硅酮、和它们的组合。 Monooleate, sorbitan monooleate, sorbitan monopalmitate, benzoate, dibutyl sebacate, diglycerides, dipropylene glycol, eugenol, fatty acids , isopropyl myristate, mineral oil, oleyl alcohol, vitamin E, triglycerides, sorbitan fatty acid ester surfactants, triethyl citrate, isoamyl acetate, chlorobutanol, turpentine, ring pentasiloxane, cyclomethicone, and combinations thereof.
8.如权利要求I中的制剂,其中所述凝固剂包括选自下列的至少一种:聚乙烯醇、聚乙烯甲基醚/马来酸酐共聚物的酯、甲基丙烯酸丁酯与甲基丙烯酸甲酯的中性共聚物、甲基丙烯酸二甲基氨基乙基酯-甲基丙烯酸丁酯-甲基丙烯酸甲酯共聚物、丙烯酸乙酯-甲基丙烯酸甲酯-三甲基氨乙基甲基丙烯酸酯氯化物的共聚物、醇溶谷蛋白(玉米醇溶蛋白)、预胶凝淀粉、乙基纤维素、鱼胶、明胶、和丙烯酸酯/辛基丙烯酰胺共聚物、乙基纤维素、羟乙基纤维素、羟甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素、甲基纤维素、聚醚酰胺、玉米淀粉、预胶凝玉米淀粉、聚醚酰胺、虫胶、聚乙烯吡咯烷酮、聚异丁烯橡胶、聚醋酸乙烯邻苯二甲酸酯、甲基丙烯酸铵、角叉菜聚糖、水性乙酸邻苯二甲酸纤维素、羧基聚亚甲基、醋酸纤维素(微晶)、纤维素 8. A formulation as claimed in claim I, wherein the coagulant comprises at least one selected from the group consisting of: polyvinyl alcohol, polyvinyl methyl ether acrylate / maleic anhydride copolymer, butyl methacrylate and methyl neutral methyl acrylate copolymers, methacrylic acid dimethylaminoethyl acrylate - butyl methacrylate - methyl methacrylate copolymer, ethyl acrylate - methyl methacrylate - trimethyl aminoethyl methacrylate chloride copolymer, prolamine (zein), pregelatinized starch, ethyl cellulose, fish glue, gelatin, and acrylate / octyl acrylamide copolymer, ethyl cellulose Su, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, polyether amides, corn starch, pregelatinized corn starch, polyether amides, shellac, polyvinyl pyrrolidone, polyisobutylene rubber, polyvinyl acetate phthalate, ammonio methacrylate, carrageenan, cellulose acetate phthalate aqueous, carboxy polymethylene methyl, cellulose acetate (microcrystalline), cellulose 合物、二乙烯基苯苯乙烯、乙烯乙酸乙烯酯、硅胶、瓜尔胶、瓜尔松脂、谷蛋白、酪蛋白、酪酸钙、酪酸铵、酪酸钠、酪酸钾、丙烯酸甲酯、微晶蜡、聚乙烯乙酸酯、PVP乙基纤维素、丙烯酸酯、PEG/PVP、黄原胶、甲硅烷氧基三甲酯、马来酸/酐共聚物、波拉克林、泊洛沙姆、聚环氧乙烷、聚G-乳酸/聚L-乳酸、萜类树脂、刺槐豆胶丙烯酸共聚物、聚氨酯分散体、糊精、聚乙烯醇-聚乙二醇共聚物、甲基丙烯酸-丙烯酸乙酯共聚物、基于甲基丙烯酸和甲基丙烯酸酯的聚合物如聚(甲基丙烯酸)、或它们的组合。 Compounds, divinyl benzene styrene, ethylene vinyl acetate, silicone, guar gum, guar Gilson fat, gluten, casein, calcium caseinate, ammonium caseinate, sodium caseinate, potassium caseinate, methyl acrylate, microcrystalline wax , polyvinyl acetate, PVP ethyl cellulose, acrylate, PEG / PVP, xanthan gum, trimethyl siloxy, maleic acid / anhydride copolymer, polacrilin, poloxamer, polyethylene ethylene oxide, G- polylactic acid / poly-L- lactic acid, terpene resin, locust bean gum, acrylic copolymers, polyurethane dispersions, dextrin, polyvinyl alcohol - polyethylene glycol copolymer, methacrylic acid - ethylacrylate ester copolymer, based on methacrylic acid and methacrylic ester polymers such as poly (methacrylic acid), or combinations thereof.
9.如权利要求I中的制剂,其中所述药物包括选自下列的至少一种:阿莫罗芬、布替萘芬、萘替芬、特比萘芬、氟康唑、伊曲康唑、酮康唑、泊沙康唑、雷夫康唑、伏立康唑、克霉唑、布康唑、益康唑、咪康唑、奥昔康唑、硫康唑、特康唑、噻康唑、卡泊芬净、米卡芬净、阿尼芬净、两性霉素B、AmB、制霉菌素、匹马菌素、灰黄霉素、环吡酮胺、卤丙炔氧苯、托萘酯、十一碳烯酸盐、阿昔洛韦、喷昔洛韦、泛昔洛韦、万乃洛韦、二十二醇、三氟尿苷、疱疹净、西多福韦、更昔洛韦、普达非洛、鬼白毒素、利巴韦林、阿巴卡韦、地拉韦啶、地达诺新、依法韦仑、拉米夫定、奈韦拉平、司他夫定、扎西他滨、齐多夫定、安瑞那韦、茚地那韦、奈非那韦、利托那韦、沙奎那韦、金刚烷胺、干扰素、奥司他韦、金刚乙胺、扎那米韦、红霉素、氯林可霉素、四环 9. The formulation of claim I, wherein said medicament comprises at least one selected from the group consisting of: amorolfine, butenafine, naftifine, terbinafine, fluconazole, itraconazole , ketoconazole, posaconazole, ravuconazole, voriconazole, clotrimazole, butoconazole, econazole, miconazole, oxiconazole, sulconazole, terconazole, tioconazole, caspofungin, micafungin, anidulafungin, amphotericin B, AmB, nystatin, pimaricin, griseofulvin, ciclopirox olamine, halo propynyl oxybenzone, tolnaftate , undecylenate, acyclovir, penciclovir, famciclovir, valacyclovir, docosanol, trifluridine, idoxuridine, cidofovir, ganciclovir, Puda felodipine, ghost white toxins, ribavirin, abacavir, delavirdine, didanosine, efavirenz, lamivudine, nevirapine, stavudine, zalcitabine, Qi and more stavudine, amprenavir, indinavir, nelfinavir, ritonavir, saquinavir, amantadine, interferon, oseltamivir, rimantadine, zanamivir, red neomycin, clindamycin, tetracyclo 素、枯草杆菌肽、新霉素、莫匹罗星、多粘菌素B、喹诺酮类如环丙沙星;利多卡因、布比卡因、罗哌卡因、丁卡因、a -2激动剂可乐定、三环抗抑郁药物、酰胺咪嗪、阿普唑仑、N-甲基-D-天冬氨酸(NMDA)拈抗剂、5-HT2A受体拈抗剂、二丙酸倍他米松、卤倍他索丙酸酯、二醋酸二氟拉松、曲安奈德、地塞米松、醋酸氟轻松、哈西奈德、糠酸莫米松、戊酸倍他米松、醋酸氟轻松、氟替卡松丙酸酯、氟轻松、氟羟可舒松、地奈德、氢化可的松丁酸酯、氢化可的松戊酸酯、二丙酸阿氯米松、氟米松Pivolate、氢化可的松、氢化可的松醋酸酯、他克莫司、皮克莫司、他扎罗汀、异维甲酸、环孢菌素、蒽林、维生素D3、胆钙化醇、骨化三醇、钙泊三醇、他卡西醇、卡泊三醇、酮洛芬、吡罗昔康、双氯芬酸、茚甲新、COX抑制剂、普通COX抑制剂、C0X-2选择性抑制剂、C0X-3选 Su, bacitracin, neomycin, mupirocin, multi polymyxin B, quinolones such as ciprofloxacin; lidocaine, bupivacaine, ropivacaine, tetracaine, a -2 agonist clonidine, tricyclic antidepressants, carbamazepine, alprazolam, N- methyl -D- aspartate (NMDA) antagonists, 5-HT2A receptor antagonists, dipropionate betamethasone, halobetasol propionate, diflorasone diacetate, triamcinolone acetonide, dexamethasone, fluocinonide, halcinonide, mometasone furoate, betamethasone valerate, fluocinolone acetonide, fluticasone propionate, fluocinolone, flurandrenolide, desonide, hydrocortisone butyrate, hydrocortisone valerate, alclometasone dipropionate, flumethasone Pivolate, hydrocortisone, hydrocortisone acetate, tacrolimus, Pike Mo Division, tazarotene, isotretinoin, cyclosporine, anthralin, vitamin D3, cholecalciferol, calcitriol, calcipotriol tacalcitol, calcipotriol, ketoprofen, piroxicam, diclofenac, indomethacin, a COX inhibitor, a COX inhibitor general, C0X-2 selective inhibitors, C0X-3 is selected from 性抑制剂、咪喹莫特、雷西莫特、水杨酸、a-羟基酸、硫磺、间苯二酚、尿素、过氧苯甲酰、尿囊素、维甲酸、三氯乙酸、乳酸、苯甲酸、孕酮、炔诺酮、醋酸炔诺酮、去氧孕烯、屈螺酮、双醋炔诺醇、诺孕曲明、诺孕酯、左炔诺孕酮、dl-甲基炔诺酮、醋酸环丙氯地孕酮、地屈孕酮、醋酸甲羟孕酮、醋酸氯地孕酮、甲地孕酮、普美孕酮、炔诺酮、利奈孕酮、孕二烯酮、7-甲异炔诺酮、雄激素类、睾酮、甲基睾丸素、氧雄龙、雄留烯二酮、二氢睾酮、雌二醇、乙炔雌二醇、雌激素、雌酮、结合雌激素、酯化雌激素、哌嗪雌酮硫酯、阿米替林、酮色林、卤倍他索丙酸酯、抗痤疮药物,和它们的组合。 Inhibitors, imiquimod, resiquimod, salicylic acid, A- hydroxy acid, sulfur, resorcinol, urea, benzoyl peroxide, allantoin, retinoic acid, trichloroacetic acid, lactic acid , benzoate, progesterone, norethindrone, norethindrone acetate, desogestrel, drospirenone, ethynodiol diacetate, norgestimate sibutramine, norgestimate, levonorgestrel, methyl DL- norethisterone, cyproterone acetate, chlormadinone, dydrogesterone, medroxyprogesterone acetate, chlormadinone acetate, megestrol, promegestone, norethindrone, lynestrenol, pregnant diene -one, 7-norethynodrel, androgens, testosterone, methyl testosterone, oxandrolone, leaving the male androstenedione, dihydrotestosterone, estradiol, ethinyl estradiol, estrogen, estrone, conjugated estrogens, esterified estrogens, piperazine estrone thioester, amitriptyline, ketanserin, halobetasol propionate, anti-acne drugs, and combinations thereof.
10.如权利要求I中的制剂,其中所述固化层足够柔软和足够粘着于所述皮肤,使得当应用于人类关节处的皮肤时,在所述关节弯曲时所述固化层在皮肤上保持基本完整至少两小时。 10. The formulation of claim I, wherein the cured layer is sufficiently soft and sufficiently adhere to the skin, so that when applied to human skin, joints, when the solidified layer remains on the skin flexion basic complete at least two hours.
11.如权利要求I中的制剂,其中所述固化层足够柔软和足够粘着于所述皮肤,使得当应用于弯曲的身体表面或身体的承重表面时,在所述弯曲的身体表面或承重表面弯曲或拉伸的情况下,所述固化层在皮肤上保持基本完整。 11. The formulation of claim I, wherein the cured layer is sufficiently soft and sufficiently adhere to the skin, so that when applied to a curved surface of the body or bearing surface of the body when the body surface or a curved bearing surface case of bending or stretching the solidified layer remains substantially intact on the skin.
12.如权利要求I中的制剂,其中所述制剂被配制,以在所述固化层形成后以治疗有效速率输送所述药物至少约2小时。 12. The formulation of claim I, wherein said formulation is formulated to deliver the therapeutically active drug at a rate of the solidified layer is formed of at least about 2 hours.
13.如权利要求I中的制剂,其中所述不挥发溶剂系统与所述凝固剂的重量比为约0. I : I 到约10 : I。 13. The formulation of claim I, wherein said non-volatile solvent system and the coagulating agent weight ratio is about 0. I: I to about 10: I.
14.如权利要求I中的制剂,其中所述不挥发溶剂系统与所述凝固剂的重量比为约0. 5 : I 到约2:1。 14. The formulation of claim I, wherein said non-volatile solvent system and the coagulating agent weight ratio is about 0. 5: I to about 2: 1.
15.如权利要求I中的制剂,其中所述固化层在标准皮肤条件和环境条件下,在应用于所述皮肤表面大约15分钟内形成。 15. The formulation of claim I, wherein said layer is cured under standard conditions and environmental conditions of the skin, is formed within about 15 minutes is applied to the skin surface.
16.如权利要求I中的制剂,其中所述制剂在皮肤应用之前具有约IOOcP到约3, 000, OOOcP的初始粘度。 16. The formulation of claim I, wherein the formulation has from about 3 to about IOOcP, 000, OOOcP initial viscosity prior to application the skin.
17.如权利要求I中的制剂,其中所述挥发性溶剂系统的重量百分数为从约10wt%到约85wt*%。 17. The formulation of claim I, wherein the weight percentage of the volatile solvent system is from about 10wt% to about 85wt *%.
18.如权利要求I中的制剂,其中所述不挥发溶剂系统包括多种不挥发溶剂并且所述不挥发溶剂的至少一种能够改善所述不挥发溶剂系统与所述凝固剂的相容性。 18. The formulation of claim I, wherein said system comprises a plurality of non-volatile solvent and the solvent does not volatilize at least one non-volatile solvent capable of improving the compatibility of the non-volatile solvent system and the coagulant .
19.如权利要求I中的制剂,其中所述固化层是粘结、柔软且连续的。 19. The formulation of claim I, wherein said adhesive layer is a cured, flexible and continuous.
20.如权利要求I中的制剂,其中所述固化层,一旦形成,是软的粘结固体,其可以以一片或相对于应用大小的仅几大片从皮肤表面上剥离。 20. The formulation of claim I wherein the cured layer in the claim, once formed, is soft coherent solid, which may be only a few or a large size relative to the application is peeled off from the skin surface.
21.如权利要求I中的制剂,其中所述固化层可以通过洗涤除去。 21. The formulation of claim I, wherein the cured layer may be removed by washing.
22.权利要求I至21中任一项所述的制剂在制备皮肤输送的药物中的应用。 I 22. transdermal delivery medicament as claimed in claim in the preparation of the formulation according to any one of claims 21 to.
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